Safety and protective efficacy of PfSPZ Vaccine administered to HIV-negative and -positive Tanzanian adults.

BACKGROUNDSanaria PfSPZ Vaccine, composed of attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), protects against malaria. We conducted this clinical trial to assess the safety and efficacy of PfSPZ Vaccine in HIV-positive (HIV+) individuals, since the HIV-infection status of participants in mass vaccination programs may be unknown.METHODSThis randomized, double-blind, placebo-controlled trial enrolled 18- to 45-year-old HIV-negative (HIV-) and well-controlled HIV+ Tanzanians (HIV viral load <40 copies/mL, CD4 counts >500 cells/µL). Participants received 5 doses of PfSPZ Vaccine or normal saline (NS) over 28 days, followed by controlled human malaria infection (CHMI) 3 weeks later.RESULTSThere were no solicited adverse events in the 9 HIV- and 12 HIV+ participants. After CHMI, 6 of 6 NS controls, 1 of 5 HIV- vaccinees, and 4 of 4 HIV+ vaccinees were Pf positive by quantitative PCR (qPCR). After immunization, anti-Pf circumsporozoite protein (anti-PfCSP) (isotype and IgG subclass) and anti-PfSPZ antibodies, anti-PfSPZ CD4+ T cell responses, and Vδ2+ γδ CD3+ T cells were nonsignificantly higher in HIV- than in HIV+ vaccinees. Sera from HIV- vaccinees had significantly higher inhibition of PfSPZ invasion of hepatocytes in vitro and antibody-dependent complement deposition (ADCD) and Fcγ3B binding by anti-PfCSP and ADCD by anti-cell-traversal protein for ookinetes and SPZ (anti-PfCelTOS) antibodies.CONCLUSIONSPfSPZ Vaccine was safe and well tolerated in HIV+ vaccinees, but not protective. Vaccine efficacy was 80% in HIV- vaccinees (P = 0.012), whose sera had significantly higher inhibition of PfSPZ invasion of hepatocytes and enrichment of multifunctional PfCSP antibodies. A more potent PfSPZ vaccine or regimen is needed to protect those living with HIV against Pf infection in Africa.TRIAL REGISTRATIONClinicalTrials.gov NCT03420053.FUNDINGEquatorial Guinea Malaria Vaccine Initiative (EGMVI), made up of the Government of Equatorial Guinea Ministries of Mines and Hydrocarbons, and Health and Social Welfare, Marathon Equatorial Guinea Production Limited, Noble Energy, Atlantic Methanol Production Company, and EG LNG; Swiss government, through ESKAS scholarship grant no. 2016.0056; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; NIH grant 1U01AI155354-01.

Population Pharmacokinetics of Antimalarial Naphthoquine in Combination with Artemisinin in Tanzanian Children and Adults: Dose Optimization.

The combination antimalarial therapy of artemisinin-naphthoquine (ART-NQ) was developed as a single-dose therapy, aiming to improve adherence relative to the multiday schedules of other artemisinin combination therapies. The pharmacokinetics of ART-NQ has not been well characterized, especially in children. A pharmacokinetic study was conducted in adults and children over 5 years of age (6 to 10, 11 to 17, and ≥18 years of age) with uncomplicated malaria in Tanzania. The median weights for the three age groups were 20, 37.5, and 55 kg, respectively. Twenty-nine patients received single doses of 20 mg/kg of body weight for artemisinin and 8 mg/kg for naphthoquine, and plasma drug concentrations were assessed at 13 time points over 42 days from treatment. We used nonlinear mixed-effects modeling to interpret the data, and allometric scaling was employed to adjust for the effect of body size. The pharmacokinetics of artemisinin was best described by one-compartment model and that of naphthoquine by a two-compartment disposition model. Clearance values for a typical patient (55-kg body weight and 44.3-kg fat-free mass) were estimated as 66.7 L/h (95% confidence interval [CI], 57.3 to 78.5 L/h) for artemisinin and 44.2 L/h (95% CI, 37.9 to 50.6 L/h) for naphthoquine. Nevertheless, we show via simulation that patients weighing ≥70 kg achieve on average a 30% lower day 7 concentration compared to a 48-kg reference patient at the doses tested, suggesting dose increases may be warranted to ensure adequate exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT01930331.).

Increase of Dose Associated With Decrease in Protection Against Controlled Human Malaria Infection by PfSPZ Vaccine in Tanzanian Adults.

BACKGROUND: A vaccine would be an ideal tool for reducing malaria's impact. PfSPZ Vaccine (radiation attenuated, aseptic, purified, cryopreserved Plasmodium falciparum [Pf] sporozoites [SPZ]) has been well tolerated and safe in >1526 malaria-naive and experienced 6-month to 65-year-olds in the United States, Europe, and Africa. When vaccine efficacy (VE) of 5 doses of 2.7 × 105 PfSPZ of PfSPZ Vaccine was assessed in adults against controlled human malaria infection (CHMI) in the United States and Tanzania and intense field transmission of heterogeneous Pf in Mali, Tanzanians had the lowest VE (20%). METHODS: To increase VE in Tanzania, we increased PfSPZ/dose (9 × 105 or 1.8 × 106) and decreased numbers of doses to 3 at 8-week intervals in a double blind, placebo-controlled trial. RESULTS: All 22 CHMIs in controls resulted in parasitemia by quantitative polymerase chain reaction. For the 9 × 105 PfSPZ group, VE was 100% (5/5) at 3 or 11 weeks (P < .000l, Barnard test, 2-tailed). For 1.8 × 106 PfSPZ, VE was 33% (2/6) at 7.5 weeks (P = .028). VE of dosage groups (100% vs 33%) was significantly different (P = .022). Volunteers underwent repeat CHMI at 37-40 weeks after last dose. 6/6 and 5/6 volunteers developed parasitemia, but time to first parasitemia was significantly longer than controls in the 9 × 105 PfSPZ group (10.89 vs 7.80 days) (P = .039), indicating a significant reduction in parasites in the liver. Antibody and T-cell responses were higher in the 1.8 × 106 PfSPZ group. CONCLUSIONS: In Tanzania, increasing the dose from 2.7 × 105 to 9 × 105 PfSPZ increased VE from 20% to 100%, but increasing to 1.8 × 106 PfSPZ significantly reduced VE. CLINICAL TRIALS REGISTRATION: NCT02613520.

Safety and Differential Antibody and T-Cell Responses to the Plasmodium falciparum Sporozoite Malaria Vaccine, PfSPZ Vaccine, by Age in Tanzanian Adults, Adolescents, Children, and Infants.

In 2016, there were more cases and deaths caused by malaria globally than in 2015. An effective vaccine would be an ideal additional tool for reducing malaria's impact. Sanaria® PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (SPZ) has been well tolerated and safe in malaria-naïve and experienced adults in the United States and Mali and protective against controlled human malaria infection with Pf in the United States and field transmission of Pf in Mali, but had not been assessed in younger age groups. We, therefore, evaluated PfSPZ Vaccine in 93 Tanzanians aged 45 years to 6 months in a randomized, double-blind, normal saline placebo-controlled trial. There were no significant differences in adverse events between vaccinees and controls or between dosage regimens. Because all age groups received three doses of 9.0 × 105 PfSPZ of PfSPZ Vaccine, immune responses were compared at this dosage. Median antibody responses against Pf circumsporozoite protein and PfSPZ were highest in infants and lowest in adults. T-cell responses were highest in 6-10-year olds after one dose and 1-5-year olds after three doses; infants had no significant positive T-cell responses. The safety data were used to support initiation of trials in > 300 infants in Kenya and Equatorial Guinea. Because PfSPZ Vaccine-induced protection is thought to be mediated by T cells, the T-cell data suggest PfSPZ Vaccine may be more protective in children than in adults, whereas infants may not be immunologically mature enough to respond to the PfSPZ Vaccine immunization regimen assessed.

Safety, Immunogenicity, and Protective Efficacy against Controlled Human Malaria Infection of Plasmodium falciparum Sporozoite Vaccine in Tanzanian Adults.

We are using controlled human malaria infection (CHMI) by direct venous inoculation (DVI) of cryopreserved, infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) to try to reduce time and costs of developing PfSPZ Vaccine to prevent malaria in Africa. Immunization with five doses at 0, 4, 8, 12, and 20 weeks of 2.7 × 105 PfSPZ of PfSPZ Vaccine gave 65% vaccine efficacy (VE) at 24 weeks against mosquito bite CHMI in U.S. adults and 52% (time to event) or 29% (proportional) VE over 24 weeks against naturally transmitted Pf in Malian adults. We assessed the identical regimen in Tanzanians for VE against PfSPZ Challenge. Twenty- to thirty-year-old men were randomized to receive five doses normal saline or PfSPZ Vaccine in a double-blind trial. Vaccine efficacy was assessed 3 and 24 weeks later. Adverse events were similar in vaccinees and controls. Antibody responses to Pf circumsporozoite protein were significantly lower than in malaria-naïve Americans, but significantly higher than in Malians. All 18 controls developed Pf parasitemia after CHMI. Four of 20 (20%) vaccinees remained uninfected after 3 week CHMI (P = 0.015 by time to event, P = 0.543 by proportional analysis) and all four (100%) were uninfected after repeat 24 week CHMI (P = 0.005 by proportional, P = 0.004 by time to event analysis). Plasmodium falciparum SPZ Vaccine was safe, well tolerated, and induced durable VE in four subjects. Controlled human malaria infection by DVI of PfSPZ Challenge appeared more stringent over 24 weeks than mosquito bite CHMI in United States or natural exposure in Malian adults, thereby providing a rigorous test of VE in Africa.

Motivations to participate in a Phase I/II HIV vaccine trial: A descriptive study from Dar es Salaam, Tanzania.

BACKGROUND: The search for an efficacious HIV vaccine is a global priority. To date only one HIV vaccine trial (RV144) has shown modest efficacy in a phase III trial. With existing different HIV-1 subtypes and frequent mutations, multiple trials are needed from different geographical sites particularly in sub-Saharan Africa where most HIV infections occur. Thus, motivations to participate in HIV vaccine trials among Tanzanians need to be assessed. This paper describes the motives of Police Officers who showed great interest to volunteer in HIVIS-03 in Dar es Salaam, Tanzania. METHODS: A descriptive cross-sectional study was conducted among Police Officers who showed interest to participate in the HIVIS-03, a phase I/II HIV vaccine trial in Dar es Salaam. Prior to detailed training sessions about HIV vaccine trials, the potential participants narrated their individual motives to participate in the trial on a piece of paper. Descriptive analysis using content approach and frequency distributions were performed. RESULTS: Of the 265 respondents, 242 (91.3%) provided their socio-demographic characteristics as well as reasons that would make them take part in the proposed trial. Majority, (39.7%), cited altruism as the main motive. Women were more likely to volunteer due to altruism compared to men (P < 0.01). Researchers' explanations about HIV/AIDS vaccine studies motivated 15.3%. More men (19.6%) than women (1.7%) were motivated to volunteer due to researchers' explanations (P < 0.001). Also, compared to other groups, those unmarried and educated up to secondary level of education were motivated to volunteer due to researchers' explanation (P < 0.05). Other reasons were: desire to become a role model (18.6%); to get knowledge for educating others (14.0%); to cooperate with researchers in developing an HIV vaccine (9.5%); to get protection against HIV infection (7.0%), and severity of the disease within families (6.2%). These results were supported by testimonies from both men and women. CONCLUSIONS: Participation in an HIV vaccine trial in a Tanzanian context is likely to be influenced by altruism and comprehensive education about the trial. Gender differences, marital status and education level need to be considered to enhance participation in future HIV vaccine trials.

Pharmacokinetic and pharmacogenomic modelling of the CYP3A activity marker 4ß-hydroxycholesterol during efavirenz treatment and efavirenz/rifampicin co-treatment.

OBJECTIVES: To assess the effect of the major efavirenz metabolizing enzyme (CYP2B6) genotype and the effects of rifampicin co-treatment on induction of CYP3A by efavirenz. PATIENTS AND METHODS: Two study arms (arm 1, n = 41 and arm 2, n = 21) were recruited into this study. In arm 1, cholesterol and 4ß-hydroxycholesterol were measured in HIV treatment-naive patients at baseline and then at 4 and 16 weeks after initiation of efavirenz-based antiretroviral therapy. In arm 2, cholesterol and 4ß-hydroxycholesterol were measured among patients taking efavirenz during rifampicin-based tuberculosis (TB) treatment (efavirenz/rifampicin) just before completion of TB treatment and then serially following completion of TB treatment (efavirenz alone). Non-linear mixed-effect modelling was performed. RESULTS: A one-compartment, enzyme turnover model described 4ß-hydroxycholesterol kinetics adequately. Efavirenz treatment in arm 1 resulted in 1.74 (relative standard error = 15%), 3.3 (relative standard error = 33.1%) and 4.0 (relative standard error = 37.1%) average fold induction of CYP3A for extensive (CYP2B6*1/*1), intermediate (CYP2B6*1/*6) and slow (CYP2B6*6/*6) efavirenz metabolizers, respectively. The rate constant of 4ß-hydroxycholesterol formation [mean (95% CI)] just before completion of TB treatment [efavirenz/rifampicin co-treatment, 7.40 × 10(-7) h(-1) (5.5 × 10(-7)-1.0 × 10(-6))] was significantly higher than that calculated 8 weeks after completion [efavirenz alone, 4.50 × 10(-7) h(-1) (4.40 × 10(-7)-4.52 × 10(-7))]. The CYP3A induction dropped to 62% of its maximum by week 8 of completion. CONCLUSIONS: Our results indicate that efavirenz induction of CYP3A is influenced by CYP2B6 genetic polymorphisms and that efavirenz/rifampicin co-treatment results in higher induction than efavirenz alone.

Nutritional status of HIV-infected women with tuberculosis in Dar es Salaam, Tanzania.

SETTING: Tuberculosis (TB) treatment clinics in Dar es Salaam, Tanzania. OBJECTIVE: To quantify anthropometrics and intake of en-ergy and protein among human immunodeficiency virus (HIV) positive women with TB. DESIGN: HIV-positive women with newly diagnosed TB were assessed on their anthropometric characteristics and dietary intake. Energy and protein intake were determined using Tanzania food composition tables and compared with standard recommendations. Patients were re-evaluated after 4-6 months of anti-tuberculosis treatment. RESULTS: Among 43 women, the baseline median CD4 count was 209 cells/µl (range 8-721); 19 (44%) had a CD4 count of <200; 20 (47%) were on antiretroviral therapy. Body mass index was <18.5 kg/m(2) in 25 (58%); the median food insecurity score was 6. The median level of kcal/day was 1693 (range 1290-2633) compared to an estimated need of 2658; the median deficit was 875 kcal (range -65-1278). The median level of protein/day was 42 g (range 27-67) compared to 77 g estimated need; the median protein deficit was 35 g (range 10-50). The median weight gain among 29 patients after 4-6 months was 6 kg. CONCLUSION: HIV-positive women with TB have substantial 24-h deficits in energy and protein intake, report significant food insecurity and gain minimal weight on anti-tuberculosis treatment. Enhanced dietary education together with daily supplementation of 1000 kcal with 40 g protein may be required.

New vaccines for the prevention of tuberculosis in human immunodeficiency virus infection.

The prevention of human immunodeficiency virus (HIV) associated tuberculosis (TB) remains challenging. Several vaccines against TB have advanced to clinical trials in patients with HIV infection. The DarDar Trial, a large, randomized, placebo-controlled efficacy trial conducted in Tanzania, has demonstrated that a multiple dose series of an inactivated whole cell mycobacterial vaccine is safe in HIV and can prevent HIV-associated TB in patients with childhood bacille Calmette-Guérin vaccination and CD4 counts of ≥200 cells/mm(3). These developments offer promise that in the not too distant future immunization with an effective vaccine against TB can be added to other strategies for the prevention of HIV-associated TB. This expanded approach is referred to as the Five 'I's': intensified case finding, infection control, isoniazid preventive therapy (IPT), initiation of antiretroviral therapy (ART), and immunization against TB. We encourage additional studies of new TB vaccines in HIV, and propose a strategy to reduce the risk of TB by integrating IPT, ART and immunization into routine HIV care. At the time of HIV diagnosis, patients with CD4 counts of ≥200 cells/mm(3) could receive immunization, IPT and, as appropriate, ART. In patients presenting with lower CD4 counts or already on ART, immunization could be initiated at CD4 counts of ≥200 cells/mm(3) to add to the protection afforded by IPT and ART.

Completion of isoniazid preventive therapy and survival in HIV-infected, TST-positive adults in Tanzania.

SETTING: The World Health Organization recommends the use of isoniazid preventive therapy (IPT) for human immunodeficiency virus (HIV) infected patients with a positive tuberculin skin test (TST). However, due to concerns about the effectiveness of IPT in community health care settings and the development of drug resistance, these recommendations have not been widely implemented in countries where tuberculosis (TB) and HIV co-infection is common. OBJECTIVE: To evaluate the effectiveness of IPT on survival and TB incidence among HIV-infected patients in Tanzania. DESIGN: A cohort study nested within a randomized trial of HIV-infected adults with baseline CD4 counts of ≥ 200 cells/µ l was conducted to compare survival and incidence of active TB between TST-positive subjects who did or did not complete 6 months of IPT in the period 2001-2008. RESULTS: Of 558 TST-positive subjects in the analytic cohort, 488 completed 6 months of IPT and 70 did not. Completers had a decrease in mortality compared to non-completers (HR 0.4, 95%CI 0.2-0.8). However, the protective effect of IPT on the incidence of active TB was non-significant (HR 0.6, 95%CI 0.3-1.3). CONCLUSION: Completion of IPT is associated with increased survival in HIV-infected adults with CD4 counts ≥ 200 cells/µ l and a positive TST.

Disseminated tuberculosis in human immunodeficiency virus infection: ineffective immunity, polyclonal disease and high mortality.

BACKGROUND: Disseminated tuberculosis (TB) is a major cause of death in patients with the acquired immune-deficiency syndrome (AIDS), but its pathogenesis and clinical features have not been defined prospectively. METHODS: Human immunodeficiency virus (HIV) infected adults with a CD4 count ≥ 200 cells/µl and bacille Calmette-Guérin scar underwent immunologic evaluation and subsequent follow-up. RESULTS: Among 20 subjects who developed disseminated TB, baseline tuberculin skin tests were ≥15 mm in 14 (70%) and lymphocyte proliferative responses to Mycobacterium tuberculosis were positive in 14 (70%). At the time of diagnosis, fever ≥2 weeks plus ≥5 kg weight loss was reported in 16 (80%) patients, abnormal chest X-rays in 7/17 (41%), and positive sputum cultures in 10 (50%); median CD4 count was 30 cells/µl (range 1-122). By insertion sequence (IS) 6110 analysis, 14 (70%) blood isolates were clustered and 3/8 (37%) concurrent sputum isolates represented a different strain (polyclonal disease). Empiric TB treatment was given to eight (40%) patients; 11 (55%) died within a month. CONCLUSIONS: Disseminated TB in HIV occurs with cellular immune responses indicating prior mycobacterial infection, and IS6110 analysis suggests an often lethal combination of reactivation and newly acquired infection. Control will require effective prevention of both remotely and recently acquired infection, and wider use of empiric therapy in patients with advanced AIDS and prolonged fever.

Low BMI and falling BMI predict HIV-associated tuberculosis: a prospective study in Tanzania.

BACKGROUND: Low body mass index (BMI) is a known risk factor for tuberculosis (TB) in people without human immunodeficiency virus (HIV), but there are no prospective studies linking BMI to the risk of HIV-associated TB. DESIGN: In HIV-infected adults with CD4 counts ≥ 200 cells/µl receiving placebo in a TB booster vaccine trial in Dar es Salaam, Tanzania, we measured BMI at baseline and Year 1, and related baseline BMI and change in BMI to the risk of developing TB. RESULTS: We documented 92 cases of TB among 979 subjects followed for a mean of 3.2 years. Compared to subjects who did not develop TB, subjects who developed TB had a lower baseline BMI (23.2 vs. 24.6 kg/m(2), P = 0.006), and a greater BMI decline from baseline to Year 1 (-0.4 vs. 0.6 kg/m(2), P < 0.001). In multivariate analyses, baseline BMI was associated with the risk of developing TB (hazard ratio [HR] per kg/m(2) 0.94, 95%CI 0.90-0.99, P = 0.028), as was the change in BMI from baseline to Year 1 (HR per kg/m(2) 0.79, 95%CI 0.71-0.87, P < 0.001). Subjects with a baseline BMI < 17 kg/m(2) were more likely to develop TB (HR 3.72, 95%CI 1.16-12.0, P = 0.028). CONCLUSION: Low and falling BMI predict HIV-associated TB.

Enhancing adherence to antiretroviral therapy at the HIV clinic in resource constrained countries; the Tanzanian experience.

OBJECTIVE: To evaluate various strategies aimed at improving adherence to antiretroviral therapy (ART). METHODS: Patients initiated on ART at Muhimbili National Hospital HIV clinic were randomly assigned to either regular adherence counseling, regular counseling plus a calendar, or regular counseling and a treatment assistant. Patients were seen monthly; during these meetings self-reported adherence to treatment was recorded. Disease progression was monitored clinically and immunologically. RESULTS: Of the 621 patients randomized, 312 received regular counseling only, 242 regular counseling and calendars, while 67 had treatment assistants in addition to regular counseling. The mean (SD) follow-up time was 14.5 (4.6) months. During follow-up 20 (3.2%) patients died, and 102 (16.4%) were lost to follow-up; this was similar in all groups. In 94.8% of all visits, patients reported to have adhered to treatment. In only 39 (0.7%) visits did patients report a < or = 95% adherence. There were no differences in adherence (P = 0.573) or differences in CD4 count and weight changes over time in the interventions. CONCLUSIONS: Good adherence to ART is possible in resource constrained countries. Persistent adherence counseling in clinic settings by itself may be effective in improving adherence to ART.

Echocardiographic patterns of juvenile rheumatic heart disease at the Kenyatta National Hospital, Nairobi.

OBJECTIVE: To describe the echocardiographic features of children with rheumatic heart disease seen at the Kenyatta National Hospital. DESIGN: A retrospective study. SETTING: The Kenyatta National Hospital Heart Unit. SUBJECTS: Patients aged 20 years and less with echocardiographic diagnosis of rheumatic heart disease. RESULTS: Two hundred and twenty four echocardiograms were analysed. Seventy six point four of cases were aged between 5 and 15 years, while on 3% were less than five years. The combinations mitral and aortic regurgitation was the most common lesion followed by isolated mitral regurgitation. Isolated aortic regurgitation was as rare as isolated mitral stenosis in the paediatric age group 1.8% and 2.7% respectively. When seen in the younger age group, the leaflet morphology in mitral regurgitation was predominantly thickening and clubbing of the leaflets while in the older children the pathology was of marked fibrosis of the sub-valvular apparatus. Leaflet prolapse and commissural fusion was the major pathology in aortic regurgitation. Pulmonary hypertension was the most common complication commonly seen in mitral valve disease. Calcification was a rare encounter in this age bracket. CONCLUSIONS: Rheumatic heart disease in the paediatric age commonly presents as isolated mitral regurgitation or in combinations of mitral and aortic regurgitation. The complications of pulmonary hypertension was predominant in mitral valve disease. Valvular calcification is rare in juvenile rheumatic heart disease.

Estimation of CD4 T-lymphocyte counts from percent CD4 T-lymphocyte determinations in HIV-1-infected subjects in sub-Saharan Africa.

The relationship between CD4 percent and CD4 count has been reported to be different in industrialized countries compared to sub-Saharan Africa, where often only the former is reliable. CD4 determinations from an open cohort of hotel workers in Dar es Salaam followed between 1990 and 1998 were evaluated. T-lymphocyte determinations were offered once a year to 190 HIV-1 seropositive, 80 seroconverters and 495 sex and age matched HIV-seronegative subjects. After log transformation of the CD4 percent and CD4 counts a good fit to a linear regression curve was found, R(2) 0.697. The CD4 percent corresponding to a CD4 count of 200 cells/mm(3) was found to be 9.8%. CD4 percent determination can be useful to estimate CD4 counts, but needs to be locally standardized. The CD4 percent in Africa corresponding to AIDS defining CD4 counts seems to be lower than in the industrialized world.

Dropouts in a long-term follow-up study involving voluntary counseling and HIV testing: experience from a cohort of police officers in Dar Es Salaam, Tanzania.

BACKGROUND: Results of most population-based studies primarily are derived from people who responded positively and thereby continued to participate in such studies. It is, however, equally important to know the characteristics of study subjects who drop out to learn the reasons that kept them from continuing to participate in the study, especially because they had initially agreed to participate in such a study. In studies with long-term follow-up, reasons for nonresponse may provide invaluable information that may be gathered through continued contact with study subjects who have withdrawn from the study. OBJECTIVES: To determine characteristics of study participants who withdrew from an ongoing study of police officers, which involved counseling and HIV testing, and to determine reasons for their discontinued participation. METHODS: Demographic characteristics of a cohort of police officers who had been participating in a study to determine their suitability for HIV vaccine trials were analyzed. Characteristics of those who did not return for the second survey of appointments for HIV testing were compared with those who continued their participation. A randomly selected sample of 132 police officers who did not participate in the second survey of HIV testing were asked why they did not return. Answers were obtained from 84 people who had discontinued their participation. RESULTS: Of eligible police officers, 2087 (72.1%) responded to the call for follow-up appointments, whereas 807 (27.9%) did not return. Those who did not return to participate in the second survey had significantly higher rates of HIV seropositivity (17.2%) than those who did return (13.5%) (p <.05). The rate of return in unmarried participants was worse (p <.05) than the rate among married participants. Rates of sexual contacts with partners other than their spouses and levels of alcohol consumption did not differ between the two groups. Reasons for dropping out of the study included fear of knowing results of HIV testing in 54.6%, lack of time to continue in 34.5%, and fears about job security in 3.6%. CONCLUSION: Fears of finding out that one might be seropositive need to be answered at recruitment, and practical arrangements must be made to facilitate further follow-up. A bias for lower incidence might be introduced in vaccine trials if participants thought to be at highest risk for HIV infection discontinue participation.

The prevalence and incidence of HIV-1 infection and syphilis in a cohort of police officers in Dar es Salaam, Tanzania: a potential population for HIV vaccine trials.

OBJECTIVES: To assess the suitability of a cohort of police officers in Dar es Salaam for HIV vaccine trials by determining the prevalence and incidence of HIV-1 infection, active syphilis and their associated factors. DESIGN AND SETTING: An open cohort study of police officers in Dar es Salaam, Tanzania. METHODS: Recruitment of police officers began in 1994. A standardized questionnaire was completed at enrolment and subsequent visits. HIV antibodies were determined using two consecutive enzyme-linked immunosorbent assays. Samples repeatedly discordant on the two tests were tested by a Western blot assay. Treponema pallidum antibodies were first determined by Venereal Disease Research Laboratory (VDRL) test and reactive sera were confirmed by Treponema pallidum hemagglutination test. RESULTS: At the end of 1996 a total of 2850 police officers had been recruited of whom 2733 (96%) consented to be tested for HIV. The overall HIV-1 seroprevalence at recruitment was 13.8% (378 of 2733). Females had a significantly higher HIV-1 seroprevalence, 18.0% (55 of 306), as compared to males, 13.3% (323 of 2427), P< 0.05. From a total of 2215 married police officers, 585 (26.4%) responded to a question on extramarital sex within the previous 3 months of whom 36.2% (212 of 585) admitted to have had at least one extramarital sexual intercourse. Condoms were not used during these encounters by 178 of 212 (84.0%). As of 31st December 1998, among the 1524 males observed for 2553 person-years (PYAR), 50 had seroconverted and among 200 females observed for 357 PYAR, eight had seroconverted. The overall crude HIV-1 incidence was thus 19.9/1000 PYAR; 19.6 and 22.4/1000 PYAR for males and females, respectively. The overall prevalence and incidence of active syphilis were 3.1% (88 of 2850) and 8.6/1000 PYAR (26 of 3149), respectively. Males had a higher prevalence of active syphilis, 84 of 2525 (3.3%) than females, five of 325 (1.5%), P = 0.09. CONCLUSIONS: There was high risk sexual practice including low condom use in this cohort of police officers. The incidence and prevalence of HIV infection were high. Police officers in Dar es Salaam are therefore a potential population group for HIV vaccine evaluation.

Isoniazid prophylaxis for tuberculosis prevention among HIV infected police officers in Dar es Salaam.

OBJECTIVE: To determine the acceptability, compliance and side effects of isoniazid (INH) prophylaxis against tuberculosis among HIV infected police officers (PO) in Dar es Salaam. DESIGN: A nested study from a prospective follow up of a cohort of police officers. SETTING: Dar es Salaam, Tanzania. SUBJECTS: One hundred and forty three HIV-1 infected police officers. MAIN OUTCOME MEASURES: Acceptance and compliance to INH prophylaxis. RESULTS: Of the 400 HIV-1 infected officers, 143 (35.7%) came forward for post-test counselling and HIV test results. Sixty per cent (87/143) of them accepted to be on INH prophylaxis. However only 42.5% (37/87) came forward for evaluation regarding their suitability for INH prophylaxis. During the evaluation, eight (21.6%) of 37 otherwise asymptomatic PO were found to have active pulmonary tuberculosis (TB). Eventually only 29 PO were actually started on INH, and only 16 (55.2%) of them completed the six months course. No serious side effects were observed. One PO developed TB two months after loss to follow up before completing the six months. CONCLUSIONS: There was low acceptability of and poor compliance with INH prophylaxis among the HIV-1 infected PO despite being educated on the benefits of prophylaxis. The prevalence of PTB among asymptomatic HIV-1 infected PO was high, and therefore persons with HIV infection should be examined for TB even in the absence of symptoms.