C. Kevin Malotte

Antiretroviral Preexposure Prophylaxis for Heterosexual HIV Transmission in Botswana

BACKGROUND Preexposure prophylaxis with antiretroviral agents has been shown to reduce the transmission of human immunodeficiency virus (HIV) among men who have sex with men; however, the efficacy among heterosexuals is uncertain. METHODS We randomly assigned HIV-seronegative men and women to receive either tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or matching placebo once daily. Monthly study visits were scheduled, and participants received a comprehensive package of prevention services, including HIV testing, counseling on adherence to medication, management of sexually transmitted infections, monitoring for adverse events, and individualized counseling on risk reduction; bone mineral density testing was performed semiannually in a subgroup of participants. RESULTS A total of 1219 men and women underwent randomization (45.7% women) and were followed for 1563 person-years (median, 1.1 years; maximum, 3.7 years). Because of low retention and logistic limitations, we concluded the study early and followed enrolled participants through an orderly study closure rather than expanding enrollment. The TDF-FTC group had higher rates of nausea (18.5% vs. 7.1%, P<0.001), vomiting (11.3% vs. 7.1%, P=0.008), and dizziness (15.1% vs. 11.0%, P=0.03) than the placebo group, but the rates of serious adverse events were similar (P=0.90). Participants who received TDF-FTC, as compared with those who received placebo, had a significant decline in bone mineral density. K65R, M184V, and A62V resistance mutations developed in 1 participant in the TDF-FTC group who had had an unrecognized acute HIV infection at enrollment. In a modified intention-to-treat analysis that included the 33 participants who became infected during the study (9 in the TDF-FTC group and 24 in the placebo group; 1.2 and 3.1 infections per 100 person-years, respectively), the efficacy of TDF-FTC was 62.2% (95% confidence interval, 21.5 to 83.4; P=0.03). CONCLUSIONS Daily TDF-FTC prophylaxis prevented HIV infection in sexually active heterosexual adults. The long-term safety of daily TDF-FTC prophylaxis, including the effect on bone mineral density, remains unknown. (Funded by the Centers for Disease Control and Prevention and the National Institutes of Health; TDF2 ClinicalTrials.gov number, NCT00448669.).

Relationships of Stigma and Shame to Gonorrhea and HIV Screening

OBJECTIVES The purpose of this study was to assess the relationships between stigma and shame associated with seeking treatment for sexually transmitted diseases (STDs) and undergoing testing for gonorrhea and HIV. METHODS Participants were 847 males and 1126 females (mean age: 24.9 years) in 7 cities. Two scales assessed STD-related stigma and STD-related shame. RESULTS Rates of stigma and shame were higher among participants without a gonorrhea test in the past year and among those without an HIV test. Sex, age, health service use, previous suspicion of gonorrhea, and low levels of stigma were independently associated with gonorrhea testing. Age, enrollment site, use of health services, gonorrhea testing, and low levels of stigma were independently associated with HIV testing. CONCLUSIONS Shame is part of the experience of seeking STD-related care, but stigma may be a more powerful barrier to obtaining such care.

Attrition in prevention research

Selective attrition can detract from the internal and external validity of longitudinal research. Four tests of selective attrition applicable to longitudinal prevention research were conducted on data bases from two recent studies. These tests assessed (1) differences between dropouts and stayers in terms of pretest indices of primary outcome variables (substance use), (2) differences in change scores for dropouts and stayers, (3) differences in rates of attrition among experimental conditions, and (4) differences in pretest indices for dropouts among conditions. Results of these analyses indicate that cigarette smokers, alcohol drinkers, and marijuana users are more likely to drop out than nonusers, limiting the external validity of both studies. For one project, differential rates of attrition among conditions suggested a possible attrition artifact which will interfere with interpretation of outcome results, possibly masking true program effectiveness. Recommendations for standardizing reports of attrition and for avoiding attrition through second efforts are made.

A Patient Education Program to Improve Adherence Rates with Antituberculosis Drug Regimens

The design, logic, and results of a two-year health education study directed at im proving rates of patient adherence to antituberculosis medical regimens are presented. An incentive scheme to reward positive health behaviors plus targeted educational coun seling sessions was implemented in a randomized clinical controlled trial. The 205 subjects who participated in the study are categorized according to patients with active tuberculosis (n = 88) or preventive patients with no evidence of active disease (n = 117). Patients in each of these groups were randomly assigned to a special intervention (SI) group or a usual care (UC) control group and were followed monthly throughout their treatment program. While SI patients with active tuberculosis demonstrated higher levels of ap pointment-keeping behavior and mean percent of medication taken compared to UC patients, no statistically significant differences between the two groups were found. Pre ventive therapy patients assigned to the SI group, however, were significantly more likely than UC patients to remain in care during their 12-month regimen (64% vs 47%; p = .003). Furthermore, SI patients had significantly higher levels of adherence to their medical regimen compared to UC patients (68% vs 38%; p < .001). These results demonstrate the positive effects of a structured health education program on the im provement of continuity of care and adherence behavior among patients with tuberculosis. This study was funded by the Centers for Disease Control through contract #200-85-0835. The assistance of the Project Clerk, Sook Hee Treadwell, the Project Health Educators, Magda Fischer, Jennifer Adams, Nancy Murray, Fred Dominguez, and the clinic staff and patients who participated in this project are gratefully acknowledged. 1. US Department of Health and Human Services, Public Health Service: The 1990 Health Objectives for the Nation: A Midcourse Review. Office of Disease Prevention and Health Promotion, 1986. 2. Centers for Disease Control. Tuberculosis—Provisional data—United States, 1986. MMWR 36: 254-255, 1987. 3. Centers for Disease Control. Tuberculosis. Final Data—United States, 1986. MMWR 36: 817-820, 1988. 4. County of Los Angeles, Department of Health Services, Public Health Programs: Communicable Disease Morbidity Report, County of Los Angeles, 1986. 5. Kopanoff DE, Snider DE, Johnson M: Recurrent tuberculosis: Why do patients develop disease again? A United States Public Health Service Cooperative Survey. Am J Public Health 78: 30-33, 1988. 6. American Thoracic Society: Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Respir Dis 134: 355-363, 1986. 7. Haynes RB: Introduction, in RB Haynes, DW Taylor, DL Sackett. (eds): Compliance in Health Care. Baltimore, Johns Hopkins University Press, 1979, pp 1-7. 8. Sackett DL, Haynes RB, editor: Compliance with Therapeutic Regimens. Baltimore, Johns Hopkins University Press, 1976. 9. Haynes RB, Taylor DW, Sackett DL, ed: Compliance in Health Care. Baltimore, Johns Hopkins University Press, 1979. 10. Meichenbaum D, Turk DC: Facilitating Treatment Adherence: A Practitioners Guidebook. Plenum Press, New York, 1987. 11. Addington WW: Patient compliance: The most serious remaining problem in the control of tuberculosis in the United States. Chest 76 (supp):741-743, 1979. 12. Report of the Committee: A Strategic Plan for the Elimination of Tuberculosis in the United States. US Department of Health and Human Services, Centers for Disease Control, May 1988. 13. Comstock GW: New data on preventive treatment with isoniazid. Annals of Internal Medicine 98:663-665, 1983. 14. Cross FS, Long MW, Banner AS, Snider DE Jr: Rifampin-isoniazid therapy of alcoholics and nonalcoholic tuberculosis patients in a U.S. Public Health Service cooperative trial. Am Rev Respir Dis 122:349-353, 1980. 15. Snider DE Jr,. Improving Patient Compliance in Tuberculosis Treatment Programs. Atlanta, U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, 1985. 16. Green LW, Kreuter MW, Deeds SG, Partridge KB: Health Education Planning: A Diagnostic Approach. Palo Alto, CA, Mayfield Publishing Company, 1980. 17. Hochbaum GM, Public Participation in Medical Science Programs: A Sociopsy chological Study. Washington, DC, United States Government Printing Office, PHS Publication No. 572, 1958. 18. Rosenstock IM: What research in motivation suggests for public health. Am J Public Health 50:295-302, 1960. 19. Becker MH: The health belief model and personal health behavior. Health Educ Monographs 2:324-473, 1974. 20. Becker MH: Sociobehavioral determinants of compliance, in DL Sackett, RB Haynes (eds): Compliance with Therapeutic Regimens. Baltimore, Johns Hopkins University Press, 1976, pp 40-50. 21. Janz NK, Becker MH: The health belief model: A decade later. Health Education Quarterly 11:1-47, 1984. 22. Sackett DL: Priorities and methods for future research, in DL Sackett, RB Haynes (eds): Compliance with Therapeutic Regimens. Baltimore, Johns Hopkins University Press, 1976, pp 169-189. 23. Dunbar JM, Stunkard AJ: Adherence to diet and drug regimen, in Levy RI, Rifkind B, Dennis B, Ernst N (eds): Nutrition, Lipids, and Coronary Heart Disease. New York, Raven Press, 1979, pp 391-423. 24. Svarstad BL: Physician-patient communication and patient conformity with medical advice, in Mechanie D (ed): The Growth of Bureaucratic Medicine. New York, John Wiley and Sons, 1976, pp 220-238. 25. Colcher IS, Bass JW: Penicillin treatment of streptococcal pharyngitis: A comparison of schedules and the role of specific counselling. JAMA 222:657-659, 1972. 26. Sharpe TR, Mikeal RL: Patient compliance with antibiotic regimens. Am J Hospital Pharm 31:479-484, 1974. 27. Swain MA, Steckel SB: Influencing adherence among hypertensives. Res Nursing and Health 4:213-222, 1981. 28. Levine DM, Green LW, Russell RP, Morisky DE, Chwalow J, Benson P: Compliance in hypertension management: What the physician can do. Practical Cardiology 5:151- 160, 1979. 29. DiMatteo MR, DiNicola DD, Achieving Patient Compliance: The Psychology of the Medical Practitioners Role. New York, Pergamon Press, 1982. 30. Eraker SA, Kirscht JP, Becker MH: Understanding and improving patient compli ance. Ann Intern Med 100:258-268, 1984. 31. Waitzkin H, Stoeckle JD: Information control and the micro-politics of health care. Soc Sci Med 10:263-276, 1976. 32. Minkler M: The use of incentives in family planning programmes: A study of com peting theories regarding their influence on attitude change. Int J Health Educ 19 (supplement):1-11, 1976. 33. Sbarbaro JA: Compliance: Inducements and enforcements. Chest 76 (supp): 750- 756, 1979. 34. Snider DE Jr, Anders HM, Pozsik CJ: Incentives to take up health services. Lancet 2:812, 1986. 35. Hull CH, Nie NH. Survival: Life Table Analysis. SPSS Update 7-9, McGraw-Hill, New York, 1981.

High Incidence of New Sexually Transmitted Infections in the Year following a Sexually Transmitted Infection: A Case for Rescreening

Context The Centers for Disease Control and Prevention recommends that women treated for Chlamydia trachomatis infection return in 3 months for evaluation of reinfection. Contribution When data from the RESPECT-2 trial were used, these investigators found that among patients treated for sexually transmitted infections, 25.8% of women and 14.7% of men acquired 1 or more new infections with Chlamydia trachomatis, Neisseria gonorrhoeae, or Trichomonas vaginalis during 1 year of follow-up. Approximately 66% of reinfections were asymptomatic. Implications Successful treatment of incident cases of sexually transmitted infections is unlikely to eliminate a reservoir of infection in the community. Physicians need to perform ongoing surveillance on men and women and encourage lifestyle changes in patients with reinfection. The Editors In 1985, the Centers for Disease Control and Prevention (CDC) treatment guidelines recommended that persons infected with Neisseria gonorrhoeae should return for a test of cure to be sure that the antibiotics had cured the infection (1). With new medications, treatment failure became rare, and by 1989, the guidelines suggested testing 1 to 2 months after treatment to detect treatment failure and reinfection (2). By 1993, the guidelines stated only that a test of cure was not recommended for N. gonorrhoeae (3). Test of cure has been unnecessary for Chlamydia trachomatis after treatment with first-line drugs, but infections detected among women several months after treatment have suggested that rescreening might be effective for detecting reinfection (3). Recent studies have found that 11% to 15% of women treated for C. trachomatis were infected when retested 3 to 4 months after treatment, possibly due to treatment failure, reinfection from an untreated partner, or infection from a new partner (46). New infections are often asymptomatic. One study with scheduled follow-up visits found that 62% of new C. trachomatis infections in men and in women were asymptomatic or unrecognized and would therefore probably be missed without rescreening (7). Untreated C. trachomatis infections can persist for years (8) and put infected women at risk for complications of asymptomatic pelvic inflammatory disease (9). In addition, transmission from asymptomatic persons may be responsible for most new infections in a community (10). The CDC has recommended that health care providers consider advising women with diagnoses of C. trachomatis infection to have another C. trachomatis test in 3 monthsnot as a test of cure but as a test for reinfection (11). We wondered whether men might also benefit from retesting, whether retesting should be expanded to include persons with N. gonorrhoeae or Trichomonas vaginalis infections (12), and whether there were other factors that clinicians could use to recommend retesting. We analyzed data from a large prevention counseling trial (13) that included baseline and 4 scheduled follow-up visits of patients in 3 sexually transmitted disease (STD) clinics to determine the incidence of new sexually transmitted infections during the year after a visit to the clinics. Methods A multicenter randomized, controlled trial of HIV prevention counseling with a rapid HIV test or a standard HIV test (RESPECT-2) was conducted in 3 public STD clinics in Denver, Colorado; Long Beach, California; and Newark, New Jersey. Primary analyses and detailed methods are described elsewhere (13). Briefly, eligible clients were those who came to the clinics for a full diagnostic examination for sexually transmitted infections, were HIV-negative at enrollment, reported having vaginal or anal sex in the preceding 3 months, and were 15 to 39 years of age. At the initial visit, participants were counseled, examined, and tested for sexually transmitted infections and HIV infection. Outcomes were measured at 13-week intervals, scheduled 3, 6, 9, and 12 months from the date of enrollment. Before each follow-up visit, study staff mailed a reminder letter to each participant and made a reminder telephone call. When participants did not keep appointments, staff mailed additional reminder letters and made additional telephone calls to reschedule the visit as needed. Participants who were due for a study follow-up visit were screened for sexually transmitted infections and were interviewed if they visited the clinic any time from 1 week before the due date up to 12 weeks after the due date. Participants were given

Relative Efficacy of Prevention Counseling With Rapid and Standard HIV Testing: A Randomized, Controlled Trial (RESPECT-2)

25 for completing each follow-up visit. This amount was later increased to

Effect of a Brief Video Intervention on Incident Infection among Patients Attending Sexually Transmitted Disease Clinics

50 in an attempt to improve retention rates. Participants were tested for C. trachomatis, N. gonorrhoeae, and T. vaginalis infections at enrollment, at each quarterly follow-up visit, and at other visits not related to the study that occurred during the 12-month follow-up period (interim visits). An incident sexually transmitted infection was defined as a positive laboratory result either preceded by a negative result for the same infection or detected more than 14 days after provision of antibiotics effective against that infection. Testing was done in the local laboratories used by each clinic. Tests for C. trachomatis and N. gonorrhoeae infections were done on urine specimens by using nucleic acid amplification tests. The sensitivity and specificity values from the package inserts for these tests are cited here; the exact values are difficult to establish because there is no gold standard for identifying infected patients (14). The Long Beach and Newark clinics used ligase chain reaction (LCx Uriprobe, Abbott Diagnostics Division, Abbott Park, Illinois); the sensitivity and specificity for C. trachomatis were 93.1% and 97.1%, respectively, and the sensitivity and specificity for N. gonorrhoeae were 97.5% and 98.3%, respectively (15, 16). The Denver clinic used polymerase chain reaction initially (Cobas Amplicor, Roche Diagnostic Systems, Inc., Branchburg, New Jersey); the sensitivity and specificity for C. trachomatis were 93.4% and 96.7%, respectively, and the sensitivity and specificity for N. gonorrhoeae were 97.1% and 98.1%, respectively (17, 18). Eighteen months later, however, this clinic changed to using strand displacement amplification (BDProbeTec ET, BD Diagnostic Systems, Sparks, Maryland); the sensitivity and specificity for C. trachomatis were 90.7% and 96.6%, respectively, and the sensitivity and specificity for N. gonorrhoeae were 96.0% and 98.8%, respectively) (19). Trichomonas vaginalis was cultured by using the InPouch TV test (BioMed Diagnostics Inc., San Jose, California) or modified Diamond medium as the culture medium. The sensitivity has been estimated at 82.4% for the InPouch TV test and 87.8% for Diamond medium; specificity for both culture methods is nearly 100% (20). Cultures were done by using vaginal swab specimens from women. At follow-up visits, vaginal swabs were collected by the participant (Denver and Long Beach) or by a clinician (Newark), depending on local clinic policy. Behavioral data were collected by using Audio Computer-Assisted Self-Interview technology at enrollment and at each scheduled study follow-up visit. For most questions, a uniform 3-month recall period was used, regardless of the time since the most recent study visit. Because previous work has shown that most new infections are asymptomatic, we limited our analysis to participants who returned for testing and therefore could be classified as infected or not infected. Return visits with testing and interviews were scheduled every 3 months, and most participants returned within 2 weeks of their scheduled time. However, some participants also returned before their scheduled visit because of concern about a possible infection. Those who returned early were tested for sexually transmitted infections and were told to return for their scheduled visit for the interview and repeated testing. All test results from interim visits between 2 interviews were associated with behaviors reported during the next scheduled interview after the interim tests. Study interviews were conducted the first time the participant returned during the scheduled follow-up time (visit 1, 84 to 174 days; visit 2, 175 to 265 days; visit 3, 266 to 356 days; and visit 4, 357 to 448 days). Test data from participants who missed interviews were grouped in the analysis with their next interview. We excluded data from visits that occurred after participants missed 2 consecutive follow-up interviews. Men who reported having sex with men in the baseline interview were also excluded because of the small sample size. Person-years at risk were calculated by using the time between interviews. Participants could contribute up to 4 intervals of observation. Those who had multiple infections with the same organism in the same interval were only counted as having 1 infection, but if an infection recurred in a different interval it was counted again. We looked for 2 types of risk factors for infection. First, we looked for characteristics that clinicians could identify during a clinic visit that might predict infection at a subsequent visit. These factors included demographic characteristics, past risk behaviors, and infections detected during that visit. Second, we looked at events that might occur during follow-up that would alert patients to a need to return for testing for sexually transmitted infections. These factors included acquiring a new partner or having sex with more than 1 partner. Multivariate analysis of factors associated with sexually transmitted infection included serial measures for each participant. We performed unconditional logistic regression using generalized estimating equations, which accounted for within-participant correlations of repeated measures (21). Because this method assumes that missing data are missing completely at random, we assessed the relationship between missing visits and response variables for all 2419 participants included in our stu

Incidence of herpes simplex virus type 2 infection in 5 sexually transmitted disease (STD) clinics and the effect of HIV/STD risk-reduction counseling

Background: Two risk-reduction counseling sessions can prevent sexually transmitted diseases (STDs); however, return rates for test results are low. Study: A randomized, controlled trial compared rapid HIV testing and counseling in 1 visit with standard HIV testing and counseling in 2 visits. Main outcomes were STDs (gonorrhea, chlamydia, trichomoniasis, syphilis, HIV) within 12 months. Participants were 15- to 39-year-old STD clinic patients in Denver, Long Beach, and Newark. STD screening and questionnaires were administered every 3 months. Results: Counseling was completed by 1632 of 1648 (99.0%) of the rapid-test group and 1144 of 1649 (69.4%) of the standard-test group. By 12 months, STD was acquired by 19.1% of the rapid group and 17.1% of the standard group (relative risk [RR], 1.11; confidence interval [CI], 0.96–1.29). STD incidence was higher in the rapid-test group than in the standard-test group among men (RR, 1.34; CI, 1.06–1.70), men who had sex with men (RR, 1.86; 95% CI, 0.92–3.76), and persons with no STDs at enrollment (RR, 1.21; 95% CI, 0.99–1.48). Behavior was similar in both groups. Conclusions: Counseling with either test had similar effects on STD incidence. For some persons, counseling with standard testing may be more effective than counseling with rapid testing.

Seroprevalence and Correlates of Herpes Simplex Virus Type 2 Infection in Five Sexually Transmitted–Disease Clinics

Background Sexually transmitted disease (STD) prevention remains a public health priority. Simple, practical interventions to reduce STD incidence that can be easily and inexpensively administered in high-volume clinical settings are needed. We evaluated whether a brief video, which contained STD prevention messages targeted to all patients in the waiting room, reduced acquisition of new infections after that clinic visit. Methods and Findings In a controlled trial among patients attending three publicly funded STD clinics (one in each of three US cities) from December 2003 to August 2005, all patients (n = 38,635) were systematically assigned to either a theory-based 23-min video depicting couples overcoming barriers to safer sexual behaviors, or the standard waiting room environment. Condition assignment alternated every 4 wk and was determined by which condition (intervention or control) was in place in the clinic waiting room during the patients first visit within the study period. An intent-to-treat analysis was used to compare STD incidence between intervention and control patients. The primary endpoint was time to diagnosis of incident laboratory-confirmed infections (gonorrhea, chlamydia, trichomoniasis, syphilis, and HIV), as identified through review of medical records and county STD surveillance registries. During 14.8 mo (average) of follow-up, 2,042 patients (5.3%) were diagnosed with incident STD (4.9%, intervention condition; 5.7%, control condition). In survival analysis, patients assigned to the intervention condition had significantly fewer STDs compared with the control condition (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.84 to 0.99). Conclusions Showing a brief video in STD clinic waiting rooms reduced new infections nearly 10% overall in three clinics. This simple, low-intensity intervention may be appropriate for adoption by clinics that serve similar patient populations. Trial registration: http://www.ClinicalTrials.gov (#NCT00137670).

Chlamydia trachomatis among Patients Infected with and Treated for Neisseria gonorrhoeae in Sexually Transmitted Disease Clinics in the United States

The seroincidence of herpes simplex virus type 2 (HSV-2) infection was determined among 1766 patients attending sexually transmitted disease (STD) clinics and enrolled in a randomized, controlled trial of human immunodeficiency virus (HIV)/STD risk-reduction counseling (RRC). Arm 1 received enhanced RRC (4 sessions); arm 2, brief RRC (2 sessions); and arm 3, the control arm, brief informational messages. The overall incidence rate was 11.7 cases/100 person-years (py). Independent predictors of incidence of HSV-2 infection included female sex; black race; residence in Newark, New Jersey; <50% condom use with an occasional partner; and, in females, incident trichomoniasis and bacterial vaginosis. Only 10.8% of new HSV-2 infections were diagnosed clinically. Incidence rates were 12.9 cases/100 py in the control arm, 11.8 cases/100 py in arm 2, and 10.3 cases/100 py in arm 1 (hazard ratio, 0.8 [95% confidence interval, 0.6-1.1], vs. controls). The possible benefit of RRC in preventing acquisition of HSV-2 infection offers encouragement that interventions more specifically tailored to genital herpes may be useful and should be an important focus of future studies.