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HLA-B*5701 and its related allele B*5703 have been shown to be strongly associated with slow HIV-1 disease progression. To elucidate the effect of these alleles fully on disease progression it is essential to identify key HIV-1 epitopes that are restricted by these alleles. Here we describe the identification of a novel HLA-B*5701, B*5703 restricted epitope within HIV-1 rev, which accounted for up to 25 and 40% of the total cytotoxic T-lymphocyte responses in two patients.

Factors that influence shedding of HIV-1 infected cells in cervical and vaginal secretions may be important determinants of sexual and vertical transmission of the virus. We investigated whether hormonal contraceptive use, vitamin A deficiency, and other variables were risk factors for cervical and vaginal shedding of HIV-infected cells.Between December, 1994, and April, 1996, women who attended a municipal sexually transmitted diseases (STDs) clinic in Mombasa, Kenya, and had previously tested positive for HIV-1, were invited to take part in our cross-sectional study. Cervical and vaginal secretions from 318 women were evaluated for the presence of HIV-1 infected cells by PCR amplification of gag DNA sequences.HIV-1 infected cells were detected in 51% of endocervical and 14% of vaginal-swab specimens. Both cervical and vaginal shedding of HIV-1 infected cells were highly associated with CD4 lymphocyte depletion (p = 0.00001 and p = 0.003, respectively). After adjustment for CD4 count, cervical proviral shedding was significantly associated with use of depot medroxyprogesterone acetate (odds ratio 2.9, 95% CI 1.5-5.7), and with use of low-dose and high-dose oral contraceptive pills (3.8, 1.4-9.9 and 12.3, 1.5-101, respectively). Vitamin A deficiency was highly predictive of vaginal HIV-1 DNA shedding. After adjustment for CD4 count, severe vitamin A deficiency, moderate deficiency, and low normal vitamin A status were associated with 12.9, 8.0, and 4.9-fold increased odds of vaginal shedding, respectively. Gonococcal cervicitis (3.1, 1.1-9.8) and vaginal candidiasis (2.6, 1.2-5.4) were also correlated with significant increases in HIV-1 DNA detection, but Chlamydia trachomatis and Trichomonas vaginalis were not.Our study documents several novel correlates of HIV-1 shedding in cervical and vaginal secretions, most notably hormonal contraceptive use and vitamin A deficiency. These factors may be important determinants of sexual or vertical transmission of HIV-1 and are of public health importance because they are easily modified by simple interventions.Correlates of HIV-1 shedding in cervical and vaginal secretions were investigated in a cross-sectional study of 318 women previously diagnosed with HIV who presented to a sexually transmitted disease clinic in Mombasa, Kenya, during 1994-96. HIV-infected cells were detected in 51% of endocervical and 14% of vaginal swab specimens. Both cervical and vaginal shedding of HIV-1 infected cells were highly associated with CD4 lymphocyte depletion. After adjustment for CD4 count, cervical proviral shedding was significantly associated with use of depo medroxyprogesterone acetate (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.5-5.7) and of low- and high-dose oral contraceptives (OR, 3.8; 95% CI, 1.4-9.9 and OR, 12.3; 95% CI, 1.5-101, respectively). After adjustment for CD4 count, severe vitamin A deficiency, moderate deficiency, and low-normal vitamin A status were associated with 12.9, 8.0, and 4.9-fold increased odds of vaginal shedding, respectively. Finally, gonococcal cervicitis (OR, 3.1; 95% CI, 1.1-9.8) and vaginal candidiasis (OR, 2.6; 95% CI, 1.2-5.4), but not Chlamydia trachomatis and Trichomonas vaginalis, were correlated with significant increases in HIV-1 DNA detection. These risk factors, easily modifiable by simple interventions, may be important determinants of sexual or vertical HIV transmission.

Objectives To determine the efficacy of isoniazid 300 mg daily for 6 months in the prevention of tuberculosis in HIV-1-infected adults and to determine whether tuberculosis preventive therapy prolongs survival in HIV-1-infected adults. Design and setting Randomized, double-blind, placebo-controlled trial in Nairobi, Kenya. Subjects Six hundred and eighty-four HIV-1-infected adults. Main outcome measures Development of tuberculosis and death. Results Three hundred and forty-two subjects received isoniazid and 342 received placebo. The median CD4 lymphocyte counts at enrolment were 322 and 346 x 10(6)/l in the isoniazid and placebo groups, respectively. The overall median follow-up from enrolment was 1.83 years (range, 0-3.4 years). The incidence of tuberculosis in the isoniazid group was 4.29 per 100 person-years (PY) of observation [95% confidence interval (CI) 2.78-6.33] and 3.86 per 100 PY of observation (95% CI, 2.45-5.79) in the placebo group, giving an adjusted rate ratio for isoniazid versus placebo of 0.92 (95% CI, 0.49-1.71). The adjusted rate ratio for tuberculosis for isoniazid versus placebo for tuberculin skin test (TST)-positive subjects was 0.60 (95% CI, 0.23-1.60) and for the TST-negative subjects, 1.23 (95% CI, 0.55-2.76). The overall adjusted mortality rate ratio for isoniazid versus placebo was 1.18 (95% CI, 0.79-1.75). Stratifying by TST reactivity gave an adjusted mortality rate ratio in those who were TST-positive of 0.33 (95% CI, 0.09-1.23) and for TST-negative subjects, 1.39 (95% CI, 0.90-2.12). Conclusions Overall there was no statistically significant protective effect of daily isoniazid for 6 months in the prevention of tuberculosis. In the TST-positive subjects, where reactivation is likely to be the more important pathogenetic mechanism, there was some protection and some reduction in mortality, although this was not statistically significant. The small number of individuals in this subgroup made the power to detect a statistically significant difference in this subgroup low. Other influences that may have diluted the efficacy of isoniazid include a high rate of transmission of new infection and rapid progression to disease or insufficient duration of isoniazid in subjects with relatively advanced immunosuppression. The rate of drug resistance observed in subjects who received isoniazid and subsequently developed tuberculosis was low.

To determine whether serum antibody to Chlamydia trachomatis antigens alters the risk of C. trachomatis pelvic inflammatory disease (PID), 280 female sex workers were prospectively evaluated over a 33-month period for incident C. trachomatis and Neisseria gonorrhoeae cervical infection and for clinical PID. At enrollment, women were tested for antibody to C. trachomatis elementary bodies by an indirect microimmunofluorescence assay and to recombinant chlamydial hsp60 (Chsp60) by an ELISA format. At each follow-up visit, women were tested for cervical chlamydial and gonococcal infection and were identified as having clinical PID if they complained of lower abdominal pain and were found to have uterine and adnexal tenderness on pelvic examination. The data demonstrate that antibody to Chsp60 predicts a 2- to 3-fold increased risk for C. trachomatis PID.

Diversity among global isolates of HIV-1 presents a formidable challenge for vaccine development. As distinct clades of the virus are recognized, it will be important to monitor their geographic distribution and divergence. In this study, we characterized HIV-1 subtypes from 17 seropositive individuals in Nairobi and Mombasa, Kenya. Seventy-one percent of viruses were clade A and 29% were clade D. The most divergent clade A isolate in our survey, Q45-CxA, grouped closely with two other taxa that were previously reported as having no distinct clade affiliation. Thus, these data may suggest the emergence of an outlier group of clade A variants or a new subtype of HIV-1. Phylogenetic relatedness of the 17 Kenyan isolates was determined separately for C2-V3 and V2 sequences of envelope and subtype designation for these isolates was independent of the region analyzed. However, evaluation of transitions, transversions, and specific character state changes indicated that mutations characterizing V2 differed from those in V3 for clade A and clade D isolates. Comparison of secondary structural characteristics of the V1-V3 region between a clade A and a clade D virus revealed conservation of motifs.The authors characterized HIV-1 subtypes from 17 seropositive individuals in Nairobi and Mombasa, Kenya. 71% of the viruses were clade A and 29% were clade D. The most divergent clade A isolate identified in the study, Q45-CxA, grouped closely with two other taxa previously reported as having no distinct clade affiliation. These findings may therefore signal the emergence of an outlier group of clade A variants or a new subtype of HIV-1. The evaluation of transitions, transversions, and specific character state changes indicated that mutations characterizing V2 differed from those in V3 for clade A and clade D isolates. Comparison of the secondary structural characteristics of the V1-V3 region between a clade A and a clade D virus revealed conservation of motifs.

The genes of the major histocompatibility complex (MHC) are amongst the most polymorphic loci known in the human population. The population genetics of the MHC encoded HLA loci of sub-Saharan Africa are of major interest because of their particular genetic diversity. Here we report on the HLA-DR 52- and 51-associated determinants of the DRB1 loci observed in 165 East African individuals studied in Nairobi, Kenya. The HLA-DR typing was done by serologic and by molecular DNA techniques (PCR-SSOP). The most frequent allele identified was DRB1*1101, followed by DRB1*1503 and DRB1*1302. Some unexpected alleles were repeatedly identified: DRB1*1108, DRB1*1316 and DRB1*1421. Most of the DR 52- and 51-associated DRB1 alleles were correctly identified by serology as part of the DR3, DR5, DR6 and DR2 groups respectively. The HLA-DRB1 profile reported here corroborates previous genetic and linguistic data supporting the concept that the Eastern African Black population is genetically distinct from other African Black populations. This has important implications in public health issues related to the genetic profile of a population (transplantation, vaccine design for example).

More than 2 million children worldwide are infected with human immunodeficiency virus type 1 (HIV-1), the majority of whom acquired the infection from their mothers [1]. Mother-to-child transmission of HIV-1 occurs in utero, intrapartum, and postnatally (through breast-feeding), with transmission rates ranging from 14% to 39% [2]. Several observations, including the differential infection rate of vaginally delivered twins, the protective effect of cesarean delivery on vertical transmission, and the association of prolonged ruptured membranes with vertical transmission, suggest that infant exposure to HIV-1 in the maternal genital tract during delivery is an important determinant of transmission [2]. The association between vertical transmission of HIV-1 and advanced maternal disease, immunosuppression, and plasma viremia or antigenemia, and the inverse association with antiretroviral therapy suggest that systemic maternal virus burden is an important factor in HIV-1 transmission [2–8]. Markers of systemic virus burden, however, may not necessarily reflect local virus burden, and the effect of genital HIV-1 shedding on vertical transmission may be distinct from the effect of plasma viremia on transmission. HIV-1 has been cultured from cell-free and cellular fractions of vaginal and endocervical secretions of HIV-1–seropositive women [9, 10]. HIV-1–infected cells are detectable in female genital tract secretions by polymerase chain reaction (PCR) amplification. The prevalence of HIV-1 DNA in cervical secretions was 33% and 37% in two previously published studies from Nairobi and 17% in vaginal specimens in one of these studies [11, 12]. Correlates of HIV-1 DNA detection in the cervix have included oral contraceptives, cervical mucopus, ectopy, and cervical inflammation [11, 12]. In addition, two studies have shown an increased prevalence of HIV-1 DNA in the cervix of pregnant women, but these studies together included only 29 pregnant women at various stages of gestation [12, 13]. While detection of HIV-1 in semen has been inversely associated with CD4 cell count and zidovudine use, little is known about these factors in female genital tract shedding of HIV-1 [14, 15]. Moreover, correlates of genital shedding of HIV-1 in pregnancy have not been described. To characterize the prevalence and correlates of HIV-1 detection in cervical and vaginal specimens from pregnant women, we evaluated HIV-1–seropositive women participating in a breast-feeding transmission study in Nairobi. Little is known about factors that predispose to virus localization within a host. We previously evaluated prevalence and correlates of HIV-1 pro virus in breast milk of women participating in this cohort [16]. To evaluate provirus shedding at different epithelial sites, we determined the relationship between HIV-1 shedding in the cervix and vagina and in breast milk.

The factors responsible for the explosive spread of human immunodeficiency virus type 1 (HIV-1) in sub-Saharan Africa continue to be identified and debated. One of the most controversial factors has been male circumcision. This cross-sectional study was conducted to measure the association between circumcision status and infection with HIV-1 among men with genital ulcer disease. Eight hundred and ten men participated in the study, of whom 190 (23%) were HIV-1-positive. A logistic regression model adjusted for behavioral and historical showed that HIV-1 positivity was independently associated with being uncircumcised (adjusted odds ratio [OR], 4.8; 95% confidence interval [CI], 3.3-7.2) and with a history of urethral discharge (adjusted OR, 2.0; 95% CI, 1.4-2.8). This association could not be explained by measures of sexual exposure to HIV-1 among this population. Male circumcision should be considered as an intervention strategy for AIDS control.

Although significant bacteriuria and urinary tract infection are more common in immunocompetent women than men, studies linking HIV immunosuppression with an increased risk of developing urinary infection have so far only been carried out in men. We therefore examined the relationship between bacteriuria and HIV status and CD 4 +cell count in a relatively homogenous cohort of female commercial sex workers (CSW) attending a community clinic in Nairobi. Two hundred and twenty-two women were enroled, and grouped according to HIV status and CD 4 count. Group 1 were HIV seronegative ( n = 52); Group 2 were HIV seropositive with CD 4 + counts above 500 × 10 6 /1 ( n = 51); Group 3 were HIV seropositive with CD 4 + counts between 201 and 500 × 10 6 /1 ( n = 67); Group 4 were HIV seropositive with CD 4 + counts below 200 × 10 6 /1 ( n = 52). Clinical signs and symptoms were noted and mid-stream specimens of urine obtained for culture and sensitivity. Overall 23% (50/222) had significant bacteriuria. The rates in each group respectively were 25%, 29%, 19% and 23% and there was no significant association between bacteriuria and HIV status; or between bacteriuria and level of immunosuppression as indicated by CD 4 + count. Overall 19% (30/222) of women had symptoms (frequency; dysuria; loin pain; smelly urine) or signs (fever; loin tenderness) compatible with urinary tract infection. However there was no significant association between symptoms or signs of infection and bacteriuria or HIV status. A typical range of pathogens, predominantly Enterobacteriaceae , were isolated and there were high rates of resistance to commonly used antimicrobials as well as 10% resistance to ciprofloxacin. Although high rates of significant bacteriuria can occur in highly sexually-active women, this appears unrelated to HIV infection or the level of HIV-related immunosuppression and is generally asymptomatic or clinically indistinct.

Beginning in April 1991 in a special treatment clinic in Nairobi Kenya 302 commercial sex workers were enrolled in a prospective study designed to examine the role of immunologic factors in Chlamydia trachomatis. They were followed for 17.6 months. The study was also intended to identify risk factors for the development of clinical pelvic inflammatory disease (PID) among women with cervical chlamydial infection. 46% (140) of the women had 317 C. trachomatis infections. 70% (102) of these women did not have chlamydial PID. 23 women had chlamydial PID. Independent risk factors for C. trachomatis PID included multiple C. trachomatis infection (odds ratio [OR] = 1.8; p = 0.0004) antibody to C. trachomatis heat-shock protein 60 (OR = 3.9; p = 0.04) and number of episodes of nongonococcal nonchlamydial PID (OR = 1.7; p = 0.02). Oral contraceptive use had an independent protective effect against chlamydial PID (OR = 0.28; p = 0.048). Among HIV-positive women a CD4 lymphocyte count of less than 400 sq m was one more independent risk factor for chlamydial PID (OR = 21.7; p = 0.036). Among human leukocyte antigen (HLA)-typed women HLA-A31 was one more independent risk factor for chlamydial PID (OR = 5.6; p = 0.043). These findings suggest that immunologic factors and oral contraceptives change host susceptibility to clinical PID among women with newly acquired C. trachomatis infection.

To evaluate the prevalence and correlates of human immunodeficiency virus (HIV)-infected cells in urethral secretions, samples were collected from 106 HIV-seropositive men with and without urethritis. HIV DNA was detected by polymerase chain reaction in 27% of 184 urethral specimens and was associated with CD4 cell depletion (P for trend,.03) and with urethritis (odds ratio [OR], 2.4 ; 95% confidence interval [CI], 1.2-4.6) or gonorrhea (OR, 2.9 ; 95% CI, 1.5-5.8). Two multivariate models were constructed that included age, CD4 cell count

Studies from Kenya have reported rapid clinical disease progression among HIV-infected professional sex workers. The reasons for this rapid decline are unknown. To better understand factors influencing the course of disease HIV-1 disease progression was explored in terms of declines in CD4 counts. Two samples from Nairobi Kenya were studied one from a cohort of female sex workers and another as a comparison group from mothers enrolled in an HIV-1 vertical transmission study. A Markov model was used to analyze transitions between HIV-1 disease stages as defined by CD4 counts. It appears that sex workers experience a rapid decline in CD4 counts consistent with earlier findings of rapid clinical disease progression among individuals in this group. The rate of decline in CD4 counts among the mothers appears to be lower. It is speculated that either intensive exposure to sexually transmitted pathogens or infection with several strains of HIV-1 may account for the rapid disease progression among female sex workers. (authors)

Objective : To assess changes in the proportion of CD4 and CD8 T-lymphocyte profiles during pregnancy, at delivery and postpartum, and to determine whether HIV-1 infection affects the normal profile. Design and methods : A total of 416 pregnant HIV-1-infected women and an age and parity-matched HIV-seronegative group of 407 pregnant women were enrolled into a prospective study on the impact of HIV-1 infection on pregnancy. Maternal blood was obtained for lymphocyte subset determination at enrolment, delivery and 6 weeks postpartum. Whole blood sample drawn in EDTA-containing tubes were used to determine T-helper/inducer (CD4) and T-suppressor/cytotoxic (CD8) cells by direct immunofluorescence using monoclonal antibodies. Results : No relationship was found between gestational age and any immunological variable. The CD4 percentage was lower postpartum than antenatally, in both HIV-1-seropositive and seronegative women, but this was not true for absolute CD4 counts. CD8 absolute counts and percentages were significantly higher postpartum than antenatally. The differences between HIV-1-seropositive and seronegative women in changes over pregnancy in CD4 and CD8 cells and their ratio, were not statistically significant. Conclusion : Our findings do not support a short-term synergistic effect of HIV-1 and pregnancy on the immune function as determined by T-lymphocyte subsets.

One hundred and sixty-two individuals from a community in Kwale District, Kenya, endemic for bancroftian filariasis, were selected for a study on the IgE response to filarial antigen (prepared from adult Brugia pahangi). Following clinical and parasitological examination, the individuals were grouped into different categories, based on the presence/absence of microfilaraemia, the presence/absence of acute or chronic (hydrocele or elephantiasis) clinical manifestations, and age. The total and filarial-specific IgE responses were evaluated in all individuals, and the responses in the various categories were compared with each other and with the responses of control groups of individuals from filariasis-free areas. The majority of individuals from the endemic area had highly elevated serum concentrations of total IgE. Overall and within each clinical category, the concentration of total IgE was higher in those individuals from the endemic area who had microfilaraemias than in those that did not. The majority of individuals from the filariasis endemic area also had significantly elevated levels of filarial-specific IgE. In contrast, the concentration of specific IgE was lower in subjects with microfilariae than in those without, irrespective of their clinical status. Only a small proportion of total IgE was filarial-specific, the mean value varying from 0.4% to 9.8%, depending on category. Among the endemic individuals, the mean proportion of total IgE which was filarial-specific was 3.6 times higher in the microfilaria-negative than in the microfilaria-positive, indicating that much of the filarial-induced IgE in microfilaraemic individuals could be non-specific. No clear relationship was observed between the IgE response and the clinical manifestations or age of the endemic individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

From a cohort of female sex workers in Nairobi, Kenya, 163 women were observed to seroconvert to human immunodeficiency virus type 1 (HIV-1) and followed to study progression to HIV-1-related disease. The effect of several covariables on disease progression was studied using a Weibull proportional hazards model. The Weibull survival model was fitted to the observed incubation times. Estimates of the median duration to CDC stage IV-A and IV-C disease were 3.5 and 4.4 years, respectively. Condom use before seroconversion was associated with a reduced risk of CDC stage IV-A disease (relative risk = .64, P < .05). The incubation time of HIV-1-related disease is extremely short in this population.

Humoral immune responses to filarial infection were investigated in 162 individuals, covering the full clinical and parasitological spectrum of bancroftian filariasis as seen in an endemic community of Kwale District, Kenya. Sera were tested for specific antifilarial antibodies (total immunoglobulins, IgM, IgGl, IgG4 and IgE) using ELISA. Most individuals showed an immunological response to the filarial antigen (prepared from adult Brugia pahangi). How these responses were related to the clinical manifestations, parasitological status and age was analysed by comparing the mean antibody levels among different categories of endemic individuals, and by comparing these to the levels in control groups from filariasis-free areas. IgM and IgE anti-filarial antibodies were detected with low specificity in unabsorbed sera. A higher specificity, clearly distinguishing the mean antibody levels in the endemic categories from those of control groups, was obtained for total specific immunoglobulins, and for IgE in sera absorbed with protein A. The most specific results were obtained for IgGl and IgG4; clear inter-category differences were observed for these classes. The mean level of specific IgG4 was significantly higher in microfilaraemic groups than in amicrofilaraemic groups, whereas the mean level of specific IgGl was significantly higher in amicrofilaraemic, symptomatic cases than in microfilaraemic, symptomatic cases. In most categories of endemic individuals, and for most antibody isotypes, the mean levels of specific antibodies tended to be higher (although not significantly) in the younger individuals than in the older individuals. Overall, the differences in the filarial antibody responses were more closely related to the presence or absence of microfilariae and to the age of the individuals than to the disease manifestations in this endemic population.

After discussing advantages and risks, only a third of the 290 HIV-infected women included in an intervention study to reduce mother-to-child transmission of HIV in Mombasa, Kenya, informed their partners of their results. Despite careful counselling, 10% subsequently experienced violence or disruption of their relationship. To increase the uptake of interventions to reduce perinatal HIV transmission safely, we recommend the involvement of partners in HIV testing. In addition, the counselling of women has to address methods and skills to deal with violence.

We sought to assess the potential acceptability of intravaginal rings (IVRs) as an HIV prevention method among at-risk women and men.We conducted a qualitative assessment of initial attitudes toward IVRs, current HIV prevention methods, and common behavioral practices among female sex workers (FSWs) and men who frequent FSWs in Mukuru, an urban slum community in Nairobi, Kenya. Nineteen women and 21 men took part in six focus group discussions.Most participants, both male and female, responded positively to the concept of an IVR as a device for delivering microbicides. Women particularly liked the convenience offered by its slow-release capacity. Some female respondents raised concerns about whether male customers would discover the ring and respond negatively, whereas others thought it unlikely that their clients would feel the ring. Focus groups conducted with male clients of FSWs suggested that many would be enthusiastic about women, and particularly sex workers, using a microbicide ring, but that women's fears about negative responses to covert use were well founded. Overall, this high-risk population of FSWs and male clients in Nairobi was very open to the IVR as a potential HIV prevention device.Themes that emerged from the focus groups highlight the importance of understanding attitudes toward IVRs as well as cultural practices that may impact IVR use in high-risk populations when pursuing clinical development of this potential HIV prevention device.

Background. Chroniccoinfectionwithherpessimplexvirustype2(HSV-2)andhumanimmunodeficiencyvirus (HIV) has been associated with an increased HIV viral load and more rapid disease progression, perhaps related to HSV-2‐associated alterations in host immunity. Methods. Studies were nested within (1) a cross-sectional study of men coinfected with HIV and HSV-2 and (2) women not infected with HIV, both before and after HSV-2 acquisition. HSV-2 infection status was determined by ELISA. HIV-specific CD8 T cell epitopes were mapped, and proliferation of HIV-specific cells was also assessed. Systemic inflammatory and regulatory T cell populations were assayed by flow cytometry. Results. The breadth of both the HIV-specific CD8 T cell interferon- and proliferative responses was reduced inparticipantscoinfectedwithHIVandHSV-2,independentoftheHIVplasmaviralloadandCD4Tcellcount,and the magnitude of the responses was also reduced. HSV-2 infection in this group was associated with increased T cell CD38 expression but not with differences in the proportion of CD4 FoxP3 regulatory T cells. However, in women not infected with HIV, acquisition of HSV-2 was associated with an increase in the proportion of regulatory T cells. Conclusions. HSV-2 coinfection was associated with reduced HIV-specific T cell responses and systemic inflammation.TheimmuneeffectsofHSV-2mayunderliethenegativeimpactthatthiscoinfectionhasontheclinicalcourse of HIV infection. Infection with herpes simplex virus type 2 (HSV-2) has been shown to affect the acquisition and subsequent course of HIV-1 (hereafter, “HIV”) in several ways. Chronic HSV-2 infection increases HIV acquisition ratesapproximately3-foldforbothmenandwomen[1] and up to 6-fold for high-risk female sex workers [2]. In sub-Saharan Africa, where the HIV pandemic has hit hardest, 60% of the general population may be infected by HSV-2 [3]. At this prevalence, it has been estimated that as many as half of the incident cases of HIV infection can be directly attributed to infection with HSV-2 [4].

Behavioral interventions in female sex workers (FSWs) are associated with changes in sexual behavior and reduced rates of sexually transmitted infections (STIs) and HIV. We examined the sustainability of such interventions. HIV-uninfected Kenyan FSWs were enrolled in a clinical trial that provided free male condoms community and clinic-based counseling and STI management. After trial completion scaled-back community-based resources remained in place. More than a year later women were invited to complete a follow-up behavioral questionnaire and to undergo STI/HIV counseling and testing. Individual changes in sexual behavior were assessed by paired analysis. One hundred seventy-two women participated in the resurvey 1.2 years after trial termination. Client numbers had risen (paired t test P < 0.001) but condom use had also increased (P < 0.001); both remained substantially lower than at enrollment. Regular partners accounted for a greater proportion of unprotected FSW sexual encounters (35% vs. 10%; P < 0.001). Only 9 (5.2%) of 172 women had a conventional STI and the follow-up HIV incidence of 1.6 per 100 person-years (PYs) was similar to that during the trial period (3.7 per 100 PYs). Incident STIs and HIV were associated with the frequency of unprotected sex and younger age. Less intensive community-based risk reduction services after clinical trial termination may support ongoing reductions in STIs and HIV among high-risk FSWs. (authors)

Background Two parallel studies evaluated safety and immunogenicity of a prophylactic HIV-1 vaccine in 192 HIV-seronegative, low-risk volunteers. Modified vaccinia virus Ankara (MVA) and plasmid DNA (pTHr) expressed HIV-1 clade A gag p24 and p17 fused to a string of 25 overlapping CD8+ T cell epitopes (HIVA). Methods These studies compared intramuscular, subcutaneous, and intradermal MVA at dosage levels ranging from 5 × 10 6 –2.5 × 10 8 pfu. In Study IAVI-010, DNA vaccine was given as a prime at months 0 and 1, followed by MVA as a boost at months 5 and 8. In Study IAVI-011, MVA alone was given at months 0 and 2. Regular safety monitoring was performed. Immunogenicity was measured by the interferon (IFN)-γ ELISPOT assay on peripheral blood mononuclear cells (PBMC). Results No serious adverse events were attributed to either vaccine; most adverse events were mild or moderate, although MVA resulted in some severe local reactions. Five vaccine recipients had at least one positive IFN-γ ELISPOT response, but none were sustained. Conclusion This HIV-1 vaccine candidate was in general safe and well-tolerated. Local reactions were common, but tolerable. Detectable immune responses were infrequent.

The ratio of retinol-binding protein (RBP) to transthyretin (TTR) has been proposed as an indirect method with which to assess vitamin A status in the context of inflammation. Few studies have been conducted among adults, and none examined the effect of HIV-1 infection. Our goal was to assess the RBP:TTR ratio among adults, including the effects of HIV-1 and the acute phase response. We used data from a cross-sectional study of 600 Kenyan women, of whom 400 had HIV-1. The effect of vitamin A supplementation among the HIV-1-infected participants was subsequently assessed in a randomized trial. Among HIV-1-uninfected women without an acute phase response, a RBP:TTR cut-off value of 0.25 had approximately 80% sensitivity and specificity to detect vitamin A deficiency (retinol

The majority of HIV-1 infections worldwide occur in Africa, where subtype B viruses are rare and intersubtype recombinants are common. Pathogenesis and vaccine studies need to focus on viruses derived from African patients, and infectious HIV-1 molecular clones can be useful tools. To clone non-B subtypes and recombinant viruses from patients, we cultivated HIV-1 from the plasma of a Kenyan long-term survivor. Viral DNA was cloned into a plasmid, which was transfected into COS cells; progeny virus was propagated in PBMCs. Sequence analyses revealed that both the patient's plasma HIV-1 RNA and the cloned DNA genomes were recombinants between subtypes D and C; subtype C sequences comprised the nef and LTR regions. The cloned virus used the CCR5 coreceptor and did not form syncytia in vitro. This infectious HIV-1 subtype D/C recombinant molecular clone obtained from a Kenyan long-term survivor promises to be useful to study pathogenesis and vaccine design.

The prospective significance of HIV-specific cytotoxic T lymphocyte (CTL) responses in highly exposed persistently seronegative populations is unknown. In 1996–1997 we screened for CTL responses against HIV clade B Env in 39 recently enrolled Kenyan female sex workers and followed these women prospectively. Annual HIV incidence was 5.8%. CTL were independently associated with age and recent HIV-1 exposure but were not prospectively associated with protection in a multivariable model that included HIV-1 exposure and duration of sex work. (excerpt)

To investigate African long-termsurvivors (LTSs) infected with non–subtype B human immunodeficiency virus type 1 (HIV- 1) we obtained full-length HIV-1 RNA sequences and immunogenetic profiles from 6 untreated women enrolled in the Pumwani Sex Worker Cohort in Nairobi Kenya. There were no discernible sequence changes likely to cause attenuation. CCR2-V64I an immunogenetic polymorphism linked to LTSs was detected in 4 women all of whom carried the HLA B58 allele. Further investigation of 99 HIV-1–infected Nairobi women found an association between CCR2-V64I and HLA B58 (P = .0048). Studying the interaction among immunogenetics immune responses and viral sequences from all HIV- 1 subtypes may increase our understanding of slow HIV-1 disease progression. (authors)

ContextSexually transmitted infections (STIs) are common in female sex workers (FSWs) and may enhance susceptibility to infection with human immunodeficiency virus type 1 (HIV-1).ObjectiveTo examine regular antibiotic prophylaxis in FSWs as a strategy for reducing the incidence of bacterial STIs and HIV-1.Design, Setting, and ParticipantsRandomized, double-blind, placebo-controlled trial conducted between 1998-2002 among FSWs in an urban slum area of Nairobi, Kenya. Of 890 FSWs screened, 466 who were seronegative for HIV-1 infection were enrolled and randomly assigned to receive azithromycin (n = 230) or placebo (n = 236). Groups were well matched at baseline for sexual risk taking and STI rates.InterventionMonthly oral administration of 1 g of azithromycin or identical placebo, as directly observed therapy. All participants were provided with free condoms, risk-reduction counseling, and STI case management.Main Outcome MeasuresThe primary study end point was incidence of HIV-1 infection. Secondary end points were the incidence of STIs due to Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, Treponema pallidum, and Haemophilus ducreyi, as well as bacterial vaginosis. Analysis of herpes simplex virus type 2 (HSV-2) infection was performed post hoc.ResultsSeventy-three percent of participants (n = 341) were followed up for 2 or more years or until they reached an administrative trial end point. Incidence of HIV-1 did not differ between treatment and placebo groups (4% [19 cases per 473 person-years of follow-up] vs 3.2% [16 cases per 495 person-years of follow-up] rate ratio [RR], 1.2; 95% CI, 0.6-2.5). Incident HIV-1 infection was associated with preceding infection with N gonorrhoeae (rate ratio [RR], 4.9; 95% CI, 1.7-14.3) or C trachomatis (RR, 3.0; 95% CI, 1.1-8.9). There was a reduced incidence in the treatment group of infection with N gonorrhoeae (RR, 0.46; 95% CI, 0.31-0.68), C trachomatis (RR, 0.38; 95% CI, 0.26-0.57), and T vaginalis (RR, 0.56; 95% CI, 0.40-0.78). The seroprevalence of HSV-2 infection at enrollment was 72.7%, and HSV-2 infection at baseline was independently associated with HIV-1 acquisition (RR, 6.3; 95% CI, 1.5-27.1).ConclusionsDespite an association between bacterial STIs and acquisition of HIV-1 infection, the addition of monthly azithromycin prophylaxis to established HIV-1 risk reduction strategies substantially reduced the incidence of STIs but did not reduce the incidence of HIV-1. Prevalent HSV-2 infection may have been an important cofactor in acquisition of HIV-1.

Background. A lack of male circumcision has been associated with increased risk of human immunodeficiency virus type 1 (HIV-1) acquisition in a number of studies but questions remain as to whether confounding by behavioral practices explains these results. The objective of the present study was to model per-sex act probabilities of female-to-male HIV-1 transmission (i.e. infectivity) for circumcised and uncircumcised men by use of detailed accounts of sexual behavior in a population with multiple partnerships. Methods. Data were collected as part of a prospective cohort study of HIV-1 acquisition among 745 Kenyan truck drivers. Sexual behavior with wives casual partners and prostitutes was recorded at quarterly follow-up visits. Published HIV-1 seroprevalence estimates among Kenyan women were used to model HIV-1 per-sex act transmission probabilities. Results. The overall probability of HIV-1 acquisition per sex act was 0.0063 (95% confidence interval 0.0035-0.0091). Female-to-male infectivity was significantly higher for uncircumcised men than for circumcised men (0.0128 vs. 0.0051; P = .04). The effect of circumcision was robust in subgroup analyses and across a wide range of HIV-1 prevalence estimates for sex partners. Conclusions. After accounting for sexual behavior we found that uncircumcised men were at a >2-fold increased risk of acquiring HIV-1 per sex act compared with circumcised men. Moreover female-to-male infectivity of HIV-1 in the context of multiple partnerships may be considerably higher than that estimated from studies of HIV-1-serodiscordant couples. These results may explain the rapid spread of the HIV-1 epidemic in settings found throughout much of Africa in which multiple partnerships and a lack of male circumcision are common. (authors)

Objective: To assess utilization of partner notification as a tool in prevention and control of Sexually transmitted infections in Nairobi City Council clinics. Design: A cross-sectional study carried out between April and September 2000. Setting: Nairobi City Council health clinics were stratified into eight administrative divisions and a total of 16 out of 54 primary health clinics with at least four STIs patients per day were selected. A standard questionnaire was administered to every fourth patient with clinical diagnosis of STIs who gave consent on exist. Sexual partners referred by index cases during the five day period from each clinic were also enrolled into the study. An additional questionnaire was administered to HCP who were managing STIs patients and their sex partners. Results: Of 407 STIs patients recruited between April and September 2000, 20.6% were primary and 2% were secondary referrals giving an average referral rate of 23%. Respondents with multiple sex partners were less likely to refer their partners compared to those who had one partner (17.9% vs 82.1%, p

Serum retinol is the most commonly used indicator of vitamin A status. Retinol is transported in a 1-to-1 complex with retinol-binding protein (RBP). RBP is easy and inexpensive to measure, and studies have shown a high correlation between concentrations of RBP and concentrations of retinol. The performance of RBP in the context of infection or protein malnutrition, however, has not been evaluated.Our aim was to determine whether RBP is a good surrogate measure for retinol in the context of HIV-1 infection, protein malnutrition, and the acute phase response.The relation between RBP and retinol was examined in a cross-sectional study of 600 Kenyan women.There was a high correlation between concentrations of RBP and those of retinol (r = 0.88). When equimolar cutoffs were used, RBP predicted marginal vitamin A status (retinol1.05 micro mol/L) with 93% sensitivity and 75% specificity and vitamin A deficiency (retinol0.70 micro mol/L) with 91% sensitivity and 94% specificity. Similarly high sensitivities and specificities were found among subgroups with HIV-1 infection, a positive acute phase response, and protein malnutrition. Protein malnutrition and a positive acute phase response were common, especially among HIV-1-infected women, and were independently and synergistically associated with lower RBP concentrations.Equimolar RBP cutoffs predict vitamin A deficiency with high sensitivity and specificity, even in the context of infection and protein malnutrition. Like retinol, RBP may not accurately identify true vitamin A status under all conditions, because the acute phase response and protein malnutrition depress RBP concentrations. However, RBP may be a simple, inexpensive tool for assessment of vitamin A deficiency in population studies.

BACKGROUND: There is increasing recognition of recombinant HIV-1 strains globally, but it has been unclear whether recombination results from superinfection during untreated, chronic infection. OBJECTIVE: To search for evidence of recombination and superinfection in Africa, where multiple HIV-1 subtypes facilitate identification of strains. METHODS: Serial blood samples from highly exposed, chronically infected women in Nairobi's Pumwani sex workers cohort were examined. Serial, complete HIV-1 RNA sequence analyses were performed for seven untreated long-term survivors. Sequences were subjected to computational analysis. RESULTS: One woman had evidence of both superinfection and recombination. Complete HIV-1 RNA sequences were first derived from plasma obtained in 1986, when the woman had been HIV seropositive for at least 21 months; this sequence was entirely subtype A. The sequences obtained from plasma in 1995 and 1997, however, were subtype A/C recombinants with a SimPlot demonstrating that the subtype A fragment in 1995 and 1997 was derived from the original 1986 A sequence. Heteroduplex tracking assays demonstrated that the subtype C sequences were not detectable as minor species in 1986. CONCLUSION: Intersubtype recombination took place between the original non-recombinant subtype A strain and the superinfecting subtype C strain in an untreated, chronically infected woman. This finding helps to explain the rising prevalence of recombinant HIV-1 worldwide. Recombination resulting from superinfection with diverse strains may pose problems for eliciting broad immune responses necessary for an effective vaccine.

Polymerase chain reaction was used to determine the prevalence and correlates of human herpesvirus 8 (HHV8) in saliva, mouth, cervical, vaginal, plasma, and peripheral-blood mononuclear cell (PBMC) samples from 174 HHV8-sero-positive female prostitutes in Mombasa, Kenya. The prevalence of detection of HHV8 was 32% in saliva samples, 28% in mouth swabs, 4% in cervical swabs, 2.3% in vaginal swabs, 9% in plasma samples, and 18% in PBMC samples. Human immunodeficiency virus type 1 (HIV-1) seropositivity was associated with detection of HHV8 from any mucosal surface (odds ratio, 2.1 [95% confidence interval, 1.1–4.0]). In HIV-1–seropositive women, there was no association between detection of HHV8 and either CD4 count or HIV-1 viral load.

BACKGROUND: CD8 T lymphocytes are important in HIV-1 control and mediate virus-specific immunity in the blood and genital tract. The induction and monitoring of mucosal CD8 cell responses will be an important component of HIV-1 vaccine trials, but information regarding the frequency, phenotype and function of genital tract CD8 cell responses is lacking. METHODS: Simultaneous blood and cervical cytobrush samples were obtained from 16 HIV-1-infected Kenyan sex workers. Epitope-specific CD8 T lymphocyte frequencies in the blood and genital tract were analysed after short-term peptide incubation and intracellular cytokine staining for interferon-gamma (IFN gamma). RESULTS: Cervical sampling resulted in adequate cell numbers for analysis in 10/16 women. Background IFN gamma production was higher in CD3+/CD8+ lymphocytes from the genital tract than from blood (0.48% versus 0.1%; P < 0.01). Responses to staphylococcal enterotoxin B were detected in cervical CD8 lymphocytes from 10/10 women, at a similar frequency to blood (16.7% in cervix and 13.3% in blood; P = 0.4). HIV-1-specific responses were detected the cervix of 8/10 women, with a trend to higher response frequencies in the genital tract than blood (2.1% versus 0.8%; P = 0.09). Co-expression of integrin CD103 (alpha E beta 7), a mucosal marker, was used to confirm the mucosal origin of cervical responses. CONCLUSIONS: Cytobrush sampling and intracellular cytokine staining is well suited to the analysis of cervical CD8 cell responses. The frequency of functional virus-specific CD3+/CD8+ T cells is similar in the genital tract and blood of HIV-1-infected women. The role of genital tract CD8 cell responses in HIV-1 control warrants further investigation.

Background: Human herpesvirus 8 (HHV-8) antibody tests vary in reported sensitivity and specificity, depending on the population tested and the assay. Objective: The purpose of this study was to compare the ability to detect seroconversion to HHV-8 in a cohort of HHV-8 seronegative female commercial sex workers in Kenya using three tests: HHV-8 viral lysate-based enzyme-linked immunosorbent assay (ELISA), an immunofluorescence assay for HHV-8 lytic antigens (IFA-lytic) and IFA for latent nuclear antigens (IFA-LANA). Study design: By ELISA, 16 women from a prospective cohort of commercial sex workers were identified as seroconverting to HHV-8. A total of 124 post-enrollment samples from these 16 women as well as the enrollment samples were tested for HHV-8 antibodies by all three assays to monitor seroconversion. Results: Of 16 women with apparent seroconversion by ELISA, 8 had a rise in IFA-lytic titers either concomitant with or prior to the first positive ELISA sample and no initial LANA by IFA. Five of the 16 women were IFA-LANA positive at entry, indicating prior infection with HHV-8. Three women had no evidence of seroconversion by either IFA-lytic or IFA-LANA and two of these three had increased ELISA reactivity concomitant with HIV-1 infection. Conclusions: Conversion from a negative to a positive ELISA result for HHV-8 antibody indicated seroconversion in only half of the study cohort of 16 women when IFA-lytic and IFA-LANA results were considered. The IFA-lytic assay was more sensitive than ELISA for early antibody responses. The IFA-LANA was positive in some women who had neither IFA-lytic nor ELISA antibodies suggesting it may be a marker for latent infections. Presumptive identification of incident HHV-8 infection by ELISA screening followed by IFA-lytic testing to confirm the positive test and IFA-LANA to rule out prior infection provides the most accurate documentation of HHV-8 seroconversion.

Objective: We examined whether HIV-1 testing using a rapid assay increases the proportion of pregnant women obtaining HIV-1 results and the uptake of perinatal HIV-1 interventions. Methods: Pregnant women attending public health clinics in Nairobi were offered voluntary counselling and testing for HIV-1. Consenting women were randomly assigned to receive either rapid or conventional HIV-1 testing. Women randomly assigned to rapid testing were allowed to receive same-day results or to return later. The results for women randomly assigned to conventional enzyme-linked immunosorbent assay (ELISA) testing were available after 7 days. HIV-1-infected women were referred for antiretroviral prophylaxis to prevent mother-to-child transmission of HIV-1. Results: Among 1282 women offered voluntary HIV-1 testing and counselling 1249 accepted testing of whom 627 were randomly assigned to rapid testing and 622 to conventional testing. The median duration between testing and obtaining results was 0 days for women who received rapid testing compared with 11 days for women who received conventional testing. The percentage receiving HIV-1 results was significantly higher among women who received rapid testing compared with conventional testing. Of 161 HIV-1-seropositive women only 24 received antiretroviral prophylaxis. The uptake of perinatal HIV-1 interventions did not differ between HIV-1-seropositive women randomly assigned to rapid testing or conventional ELISA testing. Conclusion: Rapid HIV-1 testing significantly increased the proportion of women receiving HIV-1 results which is important for sexual and perinatal HIV-1 prevention. The challenge remains to improve the uptake of perinatal HIV-1 interventions among HIV-1-seropositive women. (author’s)

Objective: To investigate the association between the cervical shedding of herpes simplex virus (HSV) and HIV-1. Design: A cross-sectional study on 200 women seropositive for both HSV-2 and HIV- 1 was conducted in a family planning clinic at the Coast Provincial General Hospital Mombasa Kenya. Main outcome measures: Quantities of HSV DNA (types 1 and 2) and HIV-1 RNA as well as the presence or absence of HIV-1 proviral DNA in cervical secretions were determined and compared. Results: There was a significant correlation between the quantities of HSV DNA and HIV-1 RNA in the cervical secretions of HSV-shedding women (Pearson’s r=0.24 P=0.05). A 10-fold increase in the quantity of cervical HSV DNA was associated with 1.35-fold higher cervical HIV-1-RNA levels (95% CI 1.00–1.81; P=0.05) and with 1.36-fold greater odds of detection of HIV-1 proviral DNA (95% CI 1.05–1.75; P=0.02). Conclusion: Higher levels of cervical HSV were associated with higher levels of expressed HIV-1 and with the more frequent detection of HIV-1-infected cells in cervical secretions. Prospective studies are needed to explore further the association between non-ulcerative cervical HSV reactivation and HIV-1 shedding. Such a relationship may have important implications for interventions designed to slow the spread of HIV-1. (author’s)

Background: Several studies have suggested that sexual transmission of human herpesvirus 8 (HHV-8) occurs among homosexual men in developed countries. However, few studies have examined heterosexual HHV-8 transmission, especially among African populations in which HHV-8 is endemic. Objectives: To determine the seroprevalence and correlates of HHV-8 infection among heterosexual African men. Design: Cross-sectional study. Methods: Participants were 1061 men enrolled in a prospective cohort study of risk factors for HIV-1 acquisition among trucking company employees in Mombasa, Kenya. Stored frozen sera from the study baseline visit were tested for antibodies to HHV-8 by whole-virus lysate ELISA. Results: HHV-8 seroprevalence was 43%. In multivariate logistic regression analysis, HHV-8 infection was independently associated with older age [for men aged 30–39 years: odds ratio (OR), 1.5; 95% confidence interval (CI), 1.1–2.0; for men aged > 40 years: OR, 1.7; 95% CI, 1.1–2.7, compared with men aged , 30 years], Christian religion (OR, 1.6; 95% CI, 1.2–2.1), being uncircumcised (OR, 1.5; 95% CI, 1.0–2.2), and ever having syphilis (OR, 2.2; 95% CI, 1.4–3.5). Ever having used condoms was associated with decreased likelihood of infection (OR, 0.7; 95% CI, 0.6–1.0). Seropositivity was not significantly related to other sexual behaviors characterized or to HIV-1 status. Conclusions: HHV-8 seropositivity is common in this population and increases with age, suggesting on-going transmission during adulthood. Infection was more common among men who were uncircumcised or who had ever had syphilis and was less common among those who had ever used condoms, suggesting that sexual factors may play a role in HHV-8 transmission. Prospective studies of HHV-8 acquisition in heterosexual African populations are needed to demonstrate whether safer sexual practices can reduce transmission.

Objectives: To investigate HLA class I allele frequencies in a Kenyan commercial sex worker (CSW) cohort, and to examine HIV-1 specific cytotoxic T lymphocyte (CTL) responses directed against epitopes derived from locally prevalent clade A virus. Methods: PCR-single strand polymorphism HLA class I typing. Sequencing of novel alleles and examination of their distribution in the CSW cohort, and a low risk HIV uninfected cohort. The peptide-binding motif of a novel class I allele was predicted, and a panel of candidate CTL epitopes was synthesized whose functional significance was examined using ELISpot and 51 Cr release assays. Results: Class I HLA-A and B frequencies within the cohort are presented. Two novel class I alleles were found, HLA-B*4415 and HLA-Cw*0407. These two class I alleles were relatively common, both in the CSW cohort (2.1 % and 3.3% respectively) and in a cohort of lower risk women (1.9% and 3.8% respectively). Allele HLA-B*4415 restricted CTL responses against a novel epitope (EEKAFSPEV) derived from p24 of clade A HIV-1, and HLA-Cw0407 restricted CTL against a predefined HLA-Cw*0401 gp120 epitope. Conclusions: Multi-epitope vaccine design requires knowledge of HLA class I distribution and HIV CTL epitope characterization in potential target populations. The description of two novel HLA class I alleles at high frequency in this high risk Kenyan CSW cohort suggests that HLA mapping of vaccine cohorts and subsequent characterization of local CTL epitopes will be warranted prior to vaccine trials.

There is an urgent need in sub-Saharan Africa to develop more effective methods of HIV prevention, including improved strategies of sexually transmitted infection (STI) prevention or an HIV vaccine, The efficacy of these strategies may be tested through clinical trials within cohorts at high risk for STI and HIV, such as female commercial sex workers. For ethical reasons, standard HIV prevention services, including access to free condoms, risk-reduction counseling, and STI therapy, will generally be offered to all study subjects. Because study subjects would often not otherwise have access to these prevention services, it is possible that enrollment in such clinical trials will itself reduce incidence rates of STI and HIV below expected levels, reducing the power to test the efficacy of the randomized intervention. We show that the provision of standard HIV prevention services as part of a randomized STI/HIV prevention trial is temporally associated with a dramatic reduction in sexual risk-taking, and that this reduction is directly associated with reduced STI incidence. This finding should be considered in the design of clinical trials with an endpoint of HIV incidence, in particular HIV preventive vaccine trials.

Objectives: To determine whether CD8 T lymphocytes from HIV-1-infected patients expressing B * 5701 and B * 5703 show broad cross-reactivity against different variants of a conserved p24 epitope, which might account for the good prognosis of HIV-1-infected individuals with HLA-B * 57. Design: B * 5701+ and B * 5703+ were recruited from Nairobi, Kenya and from Oxford, UK. All patients had been HIV positive for at least 8 years and could be categorized as slow progressors. Methods: CD8 cytotoxic T cell clones were generated from B * 5701+ and B * 5703+ donors and tested for their ability to recognize clade variants of an index p24 epitope in standard cytolytic assays. Cross-reactive responses in freshly isolated peripheral blood mononuclear cells (PBMC) were assessed by interferon-y (IFNγ) production and tetramer binding. Results: Broad cross-clade reactivity for both cytolysis and tetramer binding was observed in CD8 T cell clones from patients harbouring the index epitope sequence. Patterns of cross-reactivity were similar in freshly isolated PBMC but varied between individuals in terms of strength and breath of responses generated. One common variant induced an unusual response with tetramer binding but often failed to induce IFNγ production, and another was a weak stimulator of both IFNγ and cytolytic activity. Conclusion: B * 5701+ and B5703+ donors demonstrate broad functional cross-reactivity to both common and rare variants of a dominant p24 epitope, which could be relevant to the association of B * 57 alleles with slow progression to AIDS.

Up to 70% of cases of pelvic inflammatory disease do not have a known cause. We recruited 115 women who had presented to a clinic for sexually transmitted diseases in Nairobi, Kenya with pelvic pain that had persisted for 14 days or less, to look for an association between Mycoplasma genitalium and endometritis. With PCR, we detected M genitalium in the cervix, endometrium, or both in nine (16%) of 58 women with histologically confirmed endometritis and in one (2%) of 57 women without endometritis (p=0.02). Our results suggest that infection with M genitalium is strongly associated with acute endometritis in this population.

Objectives: To determine the effect of the HIV epidemic on invasive cervical cancer in Kenya. Methods: Of the 3902 women who were diagnosed with reproductive tract malignancies at Kenyatta National Hospital (KNH) from 1989 to 1998, 85% had invasive cervical cancer. Age at presentation and severity of cervical cancer were studied for a 9-year period when national HIV prevalence went from 5% to 5–10%, to 10–15%. Results: There was no significant change in either age at presentation or severity of cervical cancer. Of the 118 (5%) women who were tested for HIV, 36 (31%) were seropositive. These women were 5 years younger at presentation than HIV-negative women. Conclusions: A two- to three-fold increase in HIV prevalence in Kenya did not seem to have a proportional effect on the incidence of cervical cancer. Yet, HIV-positive women who presented with cervical cancer were significantly younger than HIV-negative women.

Cross-sectional analyses have demonstrated an association between use of hormonal contraceptives and shedding of herpes simplex virus (HSV). This prospective study evaluated the effect of initiating use of hormonal contraception on cervical HSV detection. Two hundred women who were seropositive for HSV-2 and human immunodeficiency virus (HIV) type 1 were examined for cervical mucosal HSV by use of quantitative DNA polymerase chain reaction before and after beginning the use of hormonal contraceptives. Cervical HSV was detected in 32 women (16.0%) before initiating and in 25 women (12.5%) after initiating use of hormonal contraception (P = .4). There were no significant differences in HSV shedding among the subgroups of women starting combination oral contraceptives containing both estrogen and progesterone or progesterone-only contraceptives. Among the 54 women who shed HSV at least once, the median change in cervical HSV after initiation of hormonal contraception was -313 copies/swab. In this prospective study, use of hormonal contraceptives did not increase detection of cervical HSV.

Objectives: To examine the relationship between use of oral contraceptive pills or depot medroxyprogesterone acetate and sexually transmitted disease acquisition. Study Design: Prospective cohort included 948 Kenyan prostitutes. Multivariate Andersen-Gill proportional hazards models were constructed, adjusting for sexual behavioral and demographic variables. Results: When compared with women who were using no contraception, users of oral contraceptive pills were at increased risk for acquisition of chlamydia (hazard ratio, 1.8; 95% confidence interval, 1.1-2.9) and vaginal candidiasis (hazard ratio, 1.5; 95% confidence interval, 1.2-1.9) and at decreased risk for bacterial vaginosis (hazard ratio, 0.8; 95% confidence interval, 0.7-1.0). Women using depot medroxyprogesterone acetate had significantly increased risk of chlamydia infection (hazard ratio, 1.6; 95% confidence interval, 1.1-2.4) and significantly decreased risk of bacterial vaginosis (hazard ratio, 0.7; 95% confidence interval, 0.5-0.8), trichomoniasis (hazard ratio, 0.6; 95% confidence interval, 0.4-1.0), and pelvic inflammatory disease (hazard ratio, 0.4; 95% confidence interval, 0.2-0.7). Consistent condom use was associated with significantly decreased risk of gonorrhea, chlamydia, genital ulcer disease, bacterial vaginosis, and pelvic inflammatory disease. Conclusions: The use of oral or injectable hormonal contraception altered susceptibility to sexually transmitted diseases, which may in turn influence transmission of human immunodeficiency virus type 1. Consistent condom use was protective with regards to sexually transmitted disease and should be encouraged for the prevention of sexually transmitted disease and human immunodeficiency virus type 1 among women who use hormonal contraception. (Am J Obstet Gynecol 2001;185:380-85)

The objective was to measure the impact on sexually transmitted infection (STI) prevalence of a female condom introduction and risk-reduction program at Kenyan agricultural sites. The authors conducted a cluster-randomized trial to determine whether a replicable community-level intervention would reduce STI prevalence. Six matched pairs of tea coffee and flower plantations were identified. The six intervention sites received an information/motivation program with free distribution of female and male condoms and six control sites received only male condoms and related information. Participants were tested for cervical gonorrhea and chlamydia by ligase chain reaction on urine specimens and vaginal trichomoniasis by culture at baseline 6 and 12 months. Participants at intervention (n = 969) and control sites (n = 960) were similar; baseline STI prevalence was 23.9%. Consistent male condom use was more than 20% at 12 months. Consistent female condom use was reported by 11 and 7% of intervention site women at 6 and 12 months. Unadjusted STI prevalence was 16.5 and 17.4% at 6 months and 18.3 and 18.5% at 12 months at the intervention and control sites respectively. Logistic regression models confirmed the null effect of the female condom intervention. Female condom introduction did not enhance STI prevention at these sites. It is unclear which aspects of the intervention--STI education condom promotion case management-- were associated with decreased STI prevalence from baseline to follow-up. (authors)

Summary Background We have completed a randomised clinical trial of breastfeeding and formula feeding to identify the frequency of breastmilk transmission of HIV-1 to infants. However, we also analysed data from this trial to examine the effect of breastfeeding on maternal death rates during 2 years after delivery. We report our findings from this secondary analysis. Methods Pregnant women attending four Nairobi city council clinics were offered HIV tests. At about 32 weeks' gestation, 425 HIV-1 seropositive women were randomly allocated to either breastfeed or formula feed their infants. After delivery, mother-infant pairs were followed up monthly during the first year and quarterly during the second year until death, or 2 years after delivery, or end of study Findings Mortality among mothers was higher in the breastfeeding group than in the formula group (18 vs 6 deaths, log rank test, p=0·009). The cumulative probability of maternal death at 24 months after delivery was 10·5% in the breastfeeding group and 3·8% in the formula group (p=0·02). The relative risk of death for breastfeeding mothers versus formula feeding mothers was 3·2 (95% CI 1·3–8·1, p=0·01). The attributable risk of maternal death due to breastfeeding was 69%. There was an association between maternal death and subsequent infant death, even after infant HIV-1 infection status was controlled for (relative risk 7·9, 95% CI 3·3–18·6, p Interpretation Our findings suggest that breastfeeding by HIV-1 infected women might result in adverse outcomes for both mother and infant.

OBJECTIVES: This study sought to assess the performance, effectiveness, and costs of a decentralized antenatal syphilis screening program in Nairobi, Kenya. METHODS: Health clinic data, quality control data, and costs were analyzed. RESULTS: The rapid plasma reagin (RPR) seroprevalence was 3.4%. In terms of screening, treatment, and partner notification, the program's performance was adequate. The program's effectiveness was problematic because of false-negative and false-positive RPR results. The cost per averted case was calculated to be US$95 to US$112. CONCLUSIONS: The sustainability of this labor-intensive program is threatened by costs and logistic constraints. Alternative strategies, such as the mass epidemiologic treatment of pregnant women in high-prevalence areas, should be considered.

There is substantial variation in susceptibility to HIV-1infection, with some subjects remaining HIV-1 seroneg-ative despite repeated exposure to virus (1–3). HIV-1–specific cytotoxic T-lymphocytes (CTLs) have beendescribed in several HIV-1–exposed, persistentlyseronegative (HEPS) populations, and the generation ofHIV-1–specific CTLs has become a key goal in the devel-opment of a protective HIV-1 vaccine (4). HIV-1–specif-ic CTLs are also found in seropositive donors, wherethey are important in suppressing viremia and prevent-ing disease progression (5–7), but are ultimately unableto prevent eventual immunosuppression and death (8).It remains unclear how HIV-1–specific CTL could playa role in protection against HIV-1 infection in HEPSsubjects, while failing to eliminate the virus in themajority of those who are infected.The epidemiology and immunology of HIV-1 hasbeen studied for over 15 years in an observationalcohort of sex workers based in the Pumwani slum areaof Nairobi, Kenya (9). It is estimated that these womenhave over 60 unprotected sexual exposures to HIV-1 peryear, resulting in intense HIV-1 infection pressure onwomen who are seronegative when joining the cohort.Rates of HIV-1 seroconversion are highest during thefirst year of cohort enrollment and reach a plateau after3 years of seronegative follow-up, although seroconver-sion may occur as late as 10 years after enrollment (10).The subgroup of women who remain both seronegativeand negative as determined by PCR for at least 3 yearswhile continuing sex work are operationally defined asHIV-1 resistant (11). HIV-1–specific CTL have beendescribed previously in both the both the blood andgenital tract of this HIV-1–resistant subgroup, usingIFN-γenzyme-linked immunospot (ELISPOT) respons-es to HIV-1 CTL epitopes (10, 12, 13), lysis of autolo-gous vaccinia HIV-1

Vitamin A is involved in normal immune function and the maintenance of mucosal integrity through complex effects on cellular differentiation.We sought to determine whether serum vitamin A levels were associated with altered susceptibility to primary infection with HIV-1 in men with high-risk sexual behaviour and genital ulcers who presented for treatment at an STD clinic in Nairobi, Kenya.HIV-1 seronegative men were prospectively followed. Vitamin A levels at study entry were compared among 38 men who HIV-1 seroconverted versus 94 controls who remained HIV seronegative.Vitamin A deficiency (retinol less than 20 microg/dl) was very common and was present in 50% of HIV-1 seroconverters versus 76% of persistent seronegatives. Seroconversion was independently associated with a retinol level greater than 20 microg/dl (HR 2.43, 95% CI 1.25-4.70, P = 0.009), and a genital ulcer aetiology caused by Haemophilus ducreyi (HR 3.49, 95% CI 1.03-11.67, P = 0.04). Circumcision was independently associated with protection (HR 0.46, 95% CI 0.23-0.93, P = 0.03).Vitamin A deficiency was not associated with an increased risk of HIV-1 infection among men with concurrent STD. A decreased risk of HIV-1 seroconversion was independently associated with lower retinol levels. The effects of vitamin A on macrophage and lymphoid cell differentiation may paradoxically increase mucosal susceptibility to HIV-1 in some vulnerable individuals, such as men with genital ulcers. Lack of circumcision and chancroid are confirmed as important co-factors for heterosexual HIV-1 transmission. The role of vitamin A in heterosexual HIV-1 transmission requires further study.

The aim was to assess the relation between selenium deficiency and vaginal or cervical shedding of HIV-1-infected cells. A cross-sectional study of 318 HIV-1 seropositive women in Mombasa Kenya was carried out. Vaginal and cervical swab specimens were tested for the presence of HIV-1 DNA by polymerase chain reaction. Multivariate logistic regression models adjusting for CD4 count and vitamin A deficiency were used. Selenium deficiency (defined as levels

As part of the ongoing study of natural HIV-1 resistance in the women of the Nairobi Sex Workers' study, we have examined a resistance-associated HLA class I allele at the molecular level. Typing by polymerase chain reaction using sequence-specific primers determined that this molecule is closely related to HLA-A*0214, one of a family of HLA-A2 supertype alleles which correlate with HIV-1 resistance in this population. Direct nucleotide sequencing shows that this molecule differs from A*0214, having a silent nucleotide substitution. We therefore propose to designate it HLA-A*02142. We have determined the peptide-binding motif of HLA-A*0214/02142 by peptide elution and bulk Edman degradative sequencing. The resulting motif, X-[Q,V]-X-X-X-K-X-X-[V,L], includes lysine as an anchor at position 6. The data complement available information on the peptide-binding characteristics of this molecule, and will be of use in identifying antigenic peptides from HIV-1 and other pathogens.