R. C. Brunham

Female to male transmission of human immunodeficiency virus type 1: risk factors for seroconversion in men

To determine the frequency and risk factors for female to male sexual transmission of human immunodeficiency virus type 1 (HIV-1), a prospective study was carried out in 422 men who had acquired a sexually transmitted disease (STD) from a group of prostitutes with a prevalence of HIV-1 infection of 85%. The initial seroprevalence of HIV among the men was 12%. 24 of 293 (8.2%) initially seronegative men seroconverted to HIV-1. Newly acquired infection was independently associated with frequent prostitute contact (risk ratio 3.2, 95% confidence interval 1.2-8.1), with the acquisition of genital ulcer disease (risk ratio 4.7, 95% confidence interval 1.3-17.0), and with being uncircumcised (risk ratio 8.2, 95% confidence interval 3.0-23.0). 96% of documented seroconversions occurred in men with one or both of the latter two risk factors. In a subgroup of 73 seronegative men who reported a single prostitute sexual contact, the frequency of HIV-1 infection was 8.2% during 12 weeks of observation. No man without a genital ulcer seroconverted. A cumulative 43% of uncircumcised men who acquired an ulcer seroconverted to HIV-1 after a single sexual exposure. These data indicate an extremely high rate of female to male transmission of HIV-1 in the presence of STD and confirm a causal relation between lack of male circumcision, genital ulcer disease, and susceptibility to HIV-1 infection.

The interaction of HIV infection and other sexually transmitted diseases: an opportunity for intervention.

In the US and Europe heterosexual intercourse appears to be an inefficient way of transmitting HIV whereas in Central Africa it is the predominant mode of transmission. The reason may lie in the fact that standard sexually-transmitted diseases which are prevalent in Africa South of the Sahara act as cofactors in HIV transmission by increasing the number of activated T4 lymphocytes. In developing countries a past history of sexually-transmitted diseases has been found in most AIDS patients -- 50% in Kinshasa 35% in Tanzania 67% in Rwanda 71% in Haiti 70% in Martinique 75% in males in Zimbabwe and 51% in females. Prostitutes are an important reservoir of sexually-transmitted diseases in Africa and HIV seropositivity among prostitutes is increasing rapidly -- 68% in Uganda and 85% in Nairobi. In both the US and Africa there is a high correlation between HIV seropositivity and a past history of syphilis especially among men. Both prospective and retrospective studies have shown an association between past history of genital ulcer disease (mainly chancroid) and HIV seropositivity. In Nairobi among 115 heterosexuals presenting with genital ulcer disease 63% of the HIV seropositives reported a prior episode of genital ulcer disease. Among 123 HIV seronegative prostitutes seroconversion to HIV-positive was significantly associated with occurrence of genital ulcer disease. A study in San Francisco showed that 68% of HIV-seronegative homosexuals became seropositive at the same time as they developed antibodies to herpes simplex type 2. There is also some evidence associating HIV seropositivity with Chlamydia trachomatis and gonorrhea. 5 US cases have been reported of rapid progression of syphilis to tertiary stage in HIV-seropositive patients. The strongest evidence indicates that genital ulcer disease (chancroid syphilis herpes) facilitates the sexual transmission of HIV. Early detection and drug therapy of bacterial sexually-transmitted diseases should be given high priority in primary health care facilities as 1 way of stemming the spread of HIV.

Chlamydia trachomatis from individuals in a sexually transmitted disease core group exhibit frequent sequence variation in the major outer membrane protein (omp1) gene.

60 cervical Chlamydia trachomatis infections identified by antigen detection from 51 prostitute women in Nairobi, Kenya were evaluated for sequence polymorphism in the major outer membrane protein (omp1) gene. DNA from clinical specimens was amplified by the polymerase chain reaction and cycle sequenced through variable domains (VD) 1, 2, and 4.37 (63%) samples had variant VD sequences, 19 (32%) samples had prototype VD sequences, and 4 (6%) samples had prototype VD sequences, and 4 (6%) samples contained omp1 sequences from two or more C. trachomatis strains. Among the 37 variant strains, 18 had two or fewer nucleotide substitutions in one or two VDs and represented point mutational drift variants. 19 strains had a larger number of nucleotide changes and displayed mosaic omp1 sequences that may have been generated by omp1 VD recombination. We conclude that the prevalence of C. trachomatis omp1 DNA polymorphism is substantial among prostitute women in Nairobi, Kenya and that this is the likely result of immune selection pressure.

EPIDEMIOLOGY OF OPHTHALMIA NEONATORUM IN KENYA

In a Nairobi hospital where ocular prophylaxis against ophthalmia neonatorum has been discontinued, 1,019 women were screened for Neisseria gonorrhoeae and Chlamydia trachomatis during labour and 7 and 28 days postpartum. The prevalence of gonococcal infection was 7% and that of chlamydial was 29%. 52.4% of gonococcal isolates produced penicillinase. The incidence of ophthalmia neonatorum was 23.2 per 100 live births, and incidences of gonococcal and chlamydial ophthalmia were 3.6 and 8.1 per 100 live births, respectively. Of 181 cases of neonatal conjunctivitis, 31% were caused by C trachomatis, 12% by N gonorrhoeae, and 3% by both. In 67 babies exposed to maternal gonococcal infection and 201 exposed to maternal chlamydial infection, rates of transmission to the eye were 42% and 31%, respectively, and to the throat were 7% and 2%. Gonococcal transmission rate was higher in mothers with concomitant chlamydial infection (68%; p = 0.01). Postpartum endometritis was associated with ophthalmia neonatorum (p less than 0.001). Ocular prophylaxis at birth for gonococcal ophthalmia should be reintroduced.

Antibody to Rmp (outer membrane protein 3) increases susceptibility to gonococcal infection.

The severe adverse effects of gonococcal infection on human fertility suggests that Neisseria gonorrhoeae would exert powerful selection for the development of a protective immune response in humans. N. gonorrhoeae is an obligate human pathogen and must persist in humans to survive. Since it is an ecologically successful organism, it must have evolved strategies to evade any human immune response it elicits. In a longitudinal study among 243 women working as prostitutes and experiencing frequent gonococcal infection, younger women, women with HIV infection, and women with antibody to the gonococcal outer membrane protein 3 (Rmp) were at increased risk of infection (adjusted odds ratio 3.4, CI95% 1.1-10.4, P < 0.05). Rmp is highly conserved in N. gonorrhoeae and the blocking of mucosal defences may be one of its functions. As similar proteins occur in many gram negative mucosal pathogens, the enhancing effect of such proteins may be a general strategy whereby bacteria evade human immune responses.

Antibodies to opacity proteins (Opa) correlate with a reduced risk of gonococcal salpingitis.

Acute salpingitis complicating cervical gonococcal infection is a significant cause of infertility. Relatively little data are available concerning the pathophysiologic mechanisms of this disease. A cohort of 243 prostitutes residing in Nairobi were followed between March 1985 and April 1988. Gonococcal cultures were performed at each visit, and acute salpingitis was diagnosed clinically. Serum at enrollment was tested by immunoblot for antibody to gonococcal outer membrane proteins. 8.6% (146/1689) of gonococcal infections were complicated by salpingitis. Increased risk of salpingitis was associated with younger age, shorter duration of prostitution, HIV infection, number of gonococcal infections, and episodes of nongonococcal salpingitis. Rmp antibody increased the risk of salpingitis. Antibody to Opa decreased the risk of salpingitis. By logistic regression analysis, antibody to Opa was independently associated with decreased risk of gonococcal salpingitis (adjusted odds ratio [OR], 0.35; 95% confidence interval [95%CI], 0.17-0.76); HIV infection (adjusted OR, 3.5; 95% CI, 0.96-12.8) and episodes of nongonococcal salpingitis (adjusted OR, 3.4; 95% CI, 1.8-6.4) were independently associated with an increased risk of salpingitis. Antibody to Opa appears to protect against ascending gonococcal infection, perhaps by interfering with Opa mediated adherence and endocytosis. The demonstration of natural immunity that protects against upper genital tract infection in women suggests that a vaccine to prevent gonococcal salpingitis is possible.

SINGLE-DOSE KANAMYCIN THERAPY OF GONOCOCCAL OPHTHALMIA NEONATORUM

117 infants with gonococcal ophthalmia neonatorum, including 27 with infections due to penicillinase-producing Neisseria gonorrhoeae, were treated as outpatients with five different regimens of single-dose intramuscular kanamycin (75 mg or 150 mg) with saline eye washes, gentamicin eye ointment, or chloramphenicol eye drops. There were no treatment failures among 68 patients treated with 75 mg or 150 mg kanamycin and gentamicin eye ointment (for 3 days). However, the minimum and maximum cumulative probabilities of cure of single-dose kanamycin with saline eye washes (for 3 days) were only 60% and 89%. 1 patient of 15 treated with 150 mg kanamycin plus chloramphenicol eye drops did not respond to treatment. Postgonococcal conjunctivitis developed in 14 (12%) infants, of whom 13 had positive cultures for Chlamydia trachomatis. Nasopharyngeal infection with N gonorrhoeae was eradicated in 9 of 11 infants colonised.

Treatment of acute pelvic inflammatory disease in the ambulatory setting: trial of cefoxitin and doxycycline versus ampicillin-sulbactam.

Ampicillin-sulbactam (750 mg) given orally twice daily for 10 days was evaluated for the treatment of acute pelvic inflammatory disease (PID) in an ambulatory setting in Nairobi, Kenya. The first 26 women received ampicillin-sulbactam in an open-label fashion, and the remaining 75 women were randomly selected to receive either ampicillin-sulbactam (n = 38) or cefoxitin (2 g) intramuscularly and probenecid (1 g) orally, followed by doxycycline (100 mg) orally twice daily for 10 days (n = 37). Women were enrolled in a sexually transmitted disease clinic and were followed for clinical and microbiologic responses at 1 to 2 weeks and 4 to 6 weeks posttreatment. Women had a later follow-up visit to note interim pregnancy or underwent hysterosalpingography for fertility outcome assessment. The short-term clinical response rates were 70% for ampicillin-sulbactam and 72% for cefoxitin-doxycycline (P = 0.47). Among Chlamydia trachomatis-infected women treated with ampicillin-sulbactam, three had microbiologic relapse. The post-PID tubal obstruction rates were similar in the two groups: 18% for ampicillin-sulbactam and 33% for cefoxitin-doxycycline (P = 0.31). Neither regimen was highly effective as a therapy for acute PID. These data strongly argue that primary prevention must be the goal for a reduction of PID morbidity and show that improved therapy for the treatment of PID in the ambulatory setting is needed.

Antimicrobial susceptibility testing and phenotyping of Neisseria gonorrhoeae isolated from patients with ophthalmia neonatorum in Nairobi, Kenya.

Antimicrobial susceptibility testing, auxotyping-serotyping, and plasmid analysis were performed on 41 ocular isolates, 7 nasopharyngeal isolates, and 18 cervical isolates of Neisseria gonorrhoeae obtained during a recent treatment trial of gonococcal ophthalmia neonatorum in Nairobi, Kenya. Fourteen distinct serovar-auxotype patterns were observed with IB-1/Pro-strains which accounted for 59% of the isolates. Infection with multiple types of gonococci appeared to occur in 22% of the mothers since 4 of 18 paired maternal cervical and neonatal ocular isolates had mismatched serovar-auxotype patterns. Among 10 treatment failure isolates only 1 had a mismatched serovar-auxotype pattern. Six (15%) of the ocular isolates were penicillinase-producing N. gonorrhoeae (PPNG). Five had the 4.4-megadalton (Md) beta-lactamase plasmid and one had the 3.2-Md beta-lactamase plasmid. The 24.5-Md plasmid was found in 5 of 6 PPNG strains and in 8 of 35 non-PPNG strains (P less than 0.02). For most antimicrobial agents, PPNG and non-PPNG strains showed similar patterns of susceptibility. Ceftriaxone was the most active of the antibiotics tested, with all strains having an MIC less than or equal to 0.06 mg/liter. Among non-PPNG strains, 15 (43%) had a penicillin MIC greater than or equal to 2 mg/liter and were considered intrinsically resistant to penicillin. Overall, non-PPNG intrinsically resistant strains had greater resistance to other antibiotics than did non-intrinsically resistant strains (P less than or equal to 0.006). The Mtr phenotype was found in 53% of these strains.