Dean B. Everett

Effect of Herpes Simplex Suppression on Incidence of HIV among Women in Tanzania

BACKGROUND Infection with herpes simplex virus type 2 (HSV-2) is associated with an increased risk of acquiring infection with the human immunodeficiency virus (HIV). This study tested the hypothesis that HSV-2 suppressive therapy reduces the risk of HIV acquisition. METHODS Female workers at recreational facilities in northwestern Tanzania who were 16 to 35 years of age were interviewed and underwent serologic testing for HIV and HSV-2. We enrolled female workers who were HIV-seronegative and HSV-2-seropositive in a randomized, double-blind, placebo-controlled trial of suppressive treatment with acyclovir (400 mg twice daily). Participants attended mobile clinics every 3 months for a follow-up period of 12 to 30 months, depending on enrollment date. The primary outcome was the incidence of infection with HIV. We used a modified intention-to-treat analysis; data for participants who became pregnant were censored. Adherence to treatment was estimated by a tablet count at each visit. RESULTS A total of 821 participants were randomly assigned to receive acyclovir (400 participants) or placebo (421 participants); 679 (83%) completed follow-up. Mean follow-up for the acyclovir and placebo groups was 1.52 and 1.62 years, respectively. The incidence of HIV infection was 4.27 per 100 person-years (27 participants in the acyclovir group and 28 in the placebo group), and there was no overall effect of acyclovir on the incidence of HIV (rate ratio for the acyclovir group, 1.08; 95% confidence interval, 0.64 to 1.83). The estimated median adherence was 90%. Genital HSV was detected in a similar proportion of participants in the two study groups at 6, 12, and 24 months. No serious adverse events were attributable to treatment with acyclovir. CONCLUSIONS These data show no evidence that acyclovir (400 mg twice daily) as HSV suppressive therapy decreases the incidence of infection with HIV. (Current Controlled Trials number, ISRCTN35385041 [controlled-trials.com].).

Biological and behavioural impact of an adolescent sexual health intervention in Tanzania : a community-randomized trial

Objective:The impact of a multicomponent intervention programme on the sexual health of adolescents was assessed in rural Tanzania. Design:A community-randomized trial. Methods:Twenty communities were randomly allocated to receive either a specially designed programme of interventions (intervention group) or standard activities (comparison group). The intervention had four components: community activities; teacher-led, peer-assisted sexual health education in years 5–7 of primary school; training and supervision of health workers to provide ‘youth-friendly’ sexual health services; and peer condom social marketing. Impacts on HIV incidence, herpes simplex virus 2 (HSV2) and other sexual health outcomes were evaluated over approximately 3 years in 9645 adolescents recruited in late 1998 before entering years 5, 6 or 7 of primary school. Results:The intervention had a significant impact on knowledge and reported attitudes, reported sexually transmitted infection symptoms, and several behavioural outcomes. Only five HIV seroconversions occurred in boys, whereas in girls the adjusted rate ratio (intervention versus comparison) was 0.75 [95% confidence interval (CI) 0.34, 1.66]. Overall HSV2 prevalences at follow-up were 11.9% in male and 21.1% in female participants, with adjusted prevalence ratios of 0.92 (CI 0.69, 1.22) and 1.05 (CI 0.83, 1.32), respectively. There was no consistent beneficial or adverse impact on other biological outcomes. The beneficial impact on knowledge and reported attitudes was confirmed by results of a school examination in a separate group of students in mid-2002. Conclusion:The intervention substantially improved knowledge, reported attitudes and some reported sexual behaviours, especially in boys, but had no consistent impact on biological outcomes within the 3-year trial period.

Prospective, multi-centre clinic-based evaluation of four rapid diagnostic tests for syphilis

Objectives: To evaluate prospectively four rapid, point-of-care serological tests for syphilis in prenatal or high risk populations in four countries. Methods: Tests were performed on consecutive clinic attenders, using whole blood in the clinic, and whole blood and serum in the laboratory. The sensitivity and specificity of each test was evaluated, using a standard treponemal test (Treponema pallidum haemagglutination assay (TPHA) or fluorescent treponemal antibody, absorbed (FTA-ABS) as gold standard. Non-treponemal tests (rapid plasma reagin (RPR) or venereal diseases research laboratory (VDRL) tests) were also performed on all subjects at three sites. Results: The specificity of each rapid test was >95% at each site. Sensitivities varied from 64–100% and, in most cases, were lower when whole blood was used rather than serum. Conclusions: Rapid serological tests for syphilis are an acceptable alternative to conventional laboratory tests. Since they do not require equipment or electricity, they could increase coverage of syphilis screening, and enable treatment to be given at the first clinic visit.

Correlates of HIV-1 genital shedding in Tanzanian women.

Background Understanding the correlates of HIV shedding is important to inform strategies to reduce HIV infectiousness. We examined correlates of genital HIV-1 RNA in women who were seropositive for both herpes simplex virus (HSV)-2 and HIV-1 and who were enrolled in a randomised controlled trial of HSV suppressive therapy (aciclovir 400 mg b.i.d vs. placebo) in Tanzania. Methodology Samples, including a cervico-vaginal lavage, were collected and tested for genital HIV-1 and HSV and reproductive tract infections (RTIs) at randomisation and 6, 12 and 24 months follow-up. Data from all women at randomisation and women in the placebo arm during follow-up were analysed using generalised estimating equations to determine the correlates of cervico-vaginal HIV-1 RNA detection and load. Principal Findings Cervico-vaginal HIV-1 RNA was detected at 52.0% of 971 visits among 482 women, and was independently associated with plasma viral load, presence of genital ulcers, pregnancy, bloody cervical or vaginal discharge, abnormal vaginal discharge, cervical ectopy, Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, an intermediate bacterial vaginosis score and HSV DNA detection. Similar factors were associated with genital HIV-1 RNA load. Conclusions RTIs were associated with increased presence and quantity of genital HIV-1 RNA in this population. These results highlight the importance of integrating effective RTI treatment into HIV care services.

Impact of Azithromycin Administration for Trachoma Control on the Carriage of Antibiotic-Resistant Streptococcus pneumoniae

ABSTRACT Community distribution of azithromycin has an important role to play in trachoma control. Previous studies have suggested that this may increase the prevalence of macrolide-resistant Streptococcus pneumoniae. S. pneumoniae was isolated from children under 7 years of age in Rombo District, northern Tanzania, before and 2 and 6 months after community-wide administration of azithromycin. Overall carriage rates were 11, 12, and 7%, respectively. Only one macrolide-resistant isolate carrying the mef gene was obtained 6 months after azithromycin administration. This contrasted with cotrimoxazole and penicillin resistance, both of which were common (cotrimoxazole resistance, 42, 43, and 47%, and penicillin resistance, 21, 17, and 16% at baseline, 2 months, and 6 months, respectively). There was a significant association between cotrimoxazole and penicillin resistance (P < 0.0001, Fishers exact). These data suggest that in communities where macrolide resistance is rare, azithromycin distribution for trachoma control is unlikely to increase the prevalence of resistant organisms.

Risk factors for herpes simplex virus type 2 and HIV among women at high risk in northwestern Tanzania - Preparing for an HSV-2 intervention trial

Objectives:To determine prevalence of and risk factors for herpes simplex virus type 2 (HSV-2) and HIV among women being screened for a randomized, controlled trial of HSV suppressive therapy in northwestern Tanzania. Methods:Two thousand seven hundred nineteen female facility workers aged 16 to 35 were interviewed and underwent serological testing for HIV and HSV-2. Factors associated with HSV-2 and HIV in women aged 16 to 24 were examined using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). Results:HSV-2 seroprevalence was 80%, and HIV seroprevalence was 30%. Among women aged 16 to 24, both infections were significantly and independently associated with older age, being a bar worker, working at a truck stop, and having more lifetime sexual partners. HSV-2 infection was also associated with lower socioeconomic status, increased alcohol intake, younger age at first sex, inconsistent condom use, and vaginal douching. There was a strong association between the 2 infections after adjustment for other factors (OR = 4.22, 95% CI: 2.6 to 6.9). Conclusions:Female facility workers in northwestern Tanzania are vulnerable to HSV-2 and HIV infections. Programs designed to increase safer sexual behavior and reduce alcohol use could be effective in reducing HSV-2 incidence and, in turn, HIV infection. This is a suitable population for an HSV suppressive therapy trial.

Ten years of surveillance for invasive Streptococcus pneumoniae during the era of antiretroviral scale-up and cotrimoxazole prophylaxis in Malawi.

Objective To document trends in invasive pneumococcal disease (IPD) in a central hospital in Malawi during the period of national scale-up of antiretroviral therapy (ART) and cotrimoxazole prophylaxis. Methods Between 1 January 2000 and 31 December 2009 almost 100,000 blood cultures and 40,000 cerebrospinal fluid (CSF) cultures were obtained from adults and children admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi with suspected severe bacterial infection. Results 4,445 pneumococcal isolates were obtained over the 10 year period. 1,837 were from children: 885 (19.9%) from blood and 952 (21.4%) from CSF. 2,608 were from adults: 1,813 (40.8%) from blood and 795 (17.9%) from CSF. At the start of the surveillance period cotrimoxazole resistance was 73.8% and at the end was 92.6%. Multidrug resistance (MDR) was present in almost one third of isolates and was constant over time. Free ART was introduced in Malawi in 2004. From 2005 onwards there was a decline in invasive pneumococcal infections with a negative correlation between ART scale-up and the decline in IPD (Pearsons correlation r = −0.91; p<0.001). Conclusion During 2004–2009, national ART scale-up in Malawi was associated with a downward trend in IPD at QECH. The introduction of cotrimoxazole prophylaxis in HIV-infected groups has not coincided with a further increase in pneumococcal cotrimoxazole or multidrug resistance. These data highlight the importance of surveillance for high disease burden infections such as IPD in the region, which will be vital for monitoring pneumococcal conjugate vaccine introduction into national immunisation programmes.

Risk factors for HIV incidence in women participating in an HSV suppressive treatment trial in Tanzania

Objectives:A randomized, double-blind, placebo-controlled trial (RCT) of herpes simplex virus type 2 suppressive therapy with acyclovir 400 mg twice daily conducted among women in northwestern Tanzania reported a similar rate of HIV acquisition in both trial arms (Current Controlled Trials number ISRCTN35385041). Risk factors for HIV incidence were examined in the context of 3-monthly follow-up visits offering both voluntary counselling and testing and care for sexually transmitted infections. Design:Prospective cohort analysis of trial participants enrolled and followed for up to 30 months. Methods:Risk factors for HIV acquisition were analysed using Cox regression. Results:Overall, 821 herpes simplex virus type 2 seropositive, HIV seronegative women were randomized; 400 randomized to acyclovir and 421 to placebo; 659 (80.3%) completed follow-up. HIV incidence was 4.27 per 100 person-years. There was no overall impact of acyclovir on HIV incidence [hazard ratio = 1.01; 95% confidence interval (CI) 0.61–1.66]. HIV acquisition was independently associated with younger age at enrolment (age 16–19 vs. 30–35: hazard ratio = 4.02; 95% CI 1.67–9.68), alcohol consumption at enrolment (≥30 drinks/week vs. none: hazard ratio = 4.39, 95% CI 1.70–11.33), having paid sex within the previous 3 months (hazard ratio = 1.82, 95% CI 1.09–3.05), recent infection with gonorrhoea (hazard ratio = 3.62, 95% CI 1.62–8.08) and injections in the previous 3 months (hazard ratio = 3.45, 95% CI 1.62–7.34). There was some evidence of an association between HIV incidence and living in the recruitment community for less than 2 years (hazard ratio = 1.75, 95% CI 0.98–3.10) and exposure to hormonal contraception (hazard ratio = 1.60, 95% CI 0.93–2.76). Conclusion:A high incidence of HIV was observed in this trial cohort, especially in young women. Interventions are needed to address the risk associated with alcohol use and to sustain control of other sexually transmitted infections.

Association of Schistosomiasis with False-Positive HIV Test Results in an African Adolescent Population

ABSTRACT This study was designed to investigate the factors associated with the high rate of false-positive test results observed with the 4th-generation Murex HIV Ag/Ab Combination EIA (enzyme immunoassay) within an adolescent and young-adult cohort in northwest Tanzania. (4th-generation assays by definition detect both HIV antigen and antibody.) The clinical and sociodemographic factors associated with false-positive HIV results were analyzed for 6,940 Tanzanian adolescents and young adults. A subsample of 284 Murex assay-negative and 240 false-positive serum samples were analyzed for immunological factors, including IgG antibodies to malaria and schistosoma parasites, heterophile antibodies, and rheumatoid factor (RF) titers. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). False-positive HIV test results were associated with evidence of other infections. False positivity was strongly associated with increasing levels of Schistosoma haematobium worm IgG1, with adolescents with optical densities in the top quartile being at the highest risk (adjusted OR = 40.7, 95% CI = 8.5 to 194.2 compared with the risk for those in the bottom quartile). False positivity was also significantly associated with increasing S. mansoni egg IgG1 titers and RF titers of ≥80 (adjusted OR = 8.2, 95% CI = 2.8 to 24.3). There was a significant negative association between Murex assay false positivity and the levels of S. mansoni worm IgG1 and IgG2 and Plasmodium falciparum IgG1 and IgG4. In Africa, endemic infections may affect the specificities of immunoassays for HIV infection. Caution should be used when the results of 4th-generation HIV test results are interpreted for African adolescent populations.

A comparison of the bactericidal activity of quinolone antibiotics in a Mycobacterium fortuitum model.

New agents are urgently needed to meet the threat of multiple drug-resistant tuberculosis and to manage infection with the naturally resistant non-tuberculosis mycobacteria. Earlier fluoroquinolones have been shown to have promising in-vitro activity, although mouse infection and clinical studies suggested that they lack sufficient bactericidal activity. Methods were evaluated to measure the bactericidal activity of fluoroquinolones and to compare the new agent moxifloxacin with other fluoroquinolones with M. fortuitum as a model system. The optimum bactericidal concentrations (OBC) for the fluoroquinolones were: moxifloxacin, 0.5 mg/L; ciprofloxacin and sparfloxacin, 2 mg/L and ofloxacin, 8 mg/L. The bactericidal indices (BI) for moxifloxacin, ciprofloxacin, sparfloxacin and ofloxacin were 1.8, 0.5, 0.2 and 0.2, respectively. Similar ranking was obtained when the time taken to produce one log10 reduction in viable count was calculated. These data indicate that moxifloxacin was the most bactericidal of the fluoroquinolones tested. Such methods provide a simple in-vitro measure that correlates with in-vivo models.