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1.  Interventions to Drive Uptake of Voluntary Medical Male Circumcision—A Collection of Impact Evaluation Evidence 
PMCID: PMC5054969  PMID: 27749597
HIV; Africa; voluntary medical male circumcision; demand generation; impact evaluation; financial compensation; VMMC
2.  Innovative Methods of Male Circumcision for HIV Prevention—Getting the Right Evidence 
World Health Organization recommends that countries with hyperendemic and generalized HIV epidemics implement voluntary medical male circumcision programs for HIV prevention. Innovative methods of male circumcision including devices have the potential to simplify the procedure, reduce time and cost, increase client acceptability, enhance safety, and expand the numbers of providers who may perform circumcision. We describe work led by World Health Organization and supported by global partners to define a pathway for the evaluation of efficacy and safety of male circumcision devices, to set priority criteria, and to establish a process to guide the use of devices in publicly funded voluntary medical male circumcision programs for HIV prevention. A device classification scheme, an expert Technical Advisory Group on Innovations in Male Circumcision, and a formal prequalification program have also guided considerations on safe use of devices. A rigorous approach was deemed appropriate given the intervention is for use among healthy men for public health purposes. The pathway and processes led to coordinated research, better standardization in research outcomes, and guidance that informed the research, introduction and implementation phases. The lessons learnt from this case study can inform evaluation and use of future public health innovations.
PMCID: PMC4936503  PMID: 27331591
male circumcision; medical devices; innovation research; implementation; prequalification; ShangRing; PrePex
3.  VMMC Devices—Introducing a New Innovation to a Public Health Intervention 
PMCID: PMC4936419  PMID: 27331583
voluntary medical male circumcision; circumcision; circumcision devices; innovation; introduction
4.  Employing Demand-Based Volumetric Forecasting to Identify Potential for and Roles of Devices in Scale-Up of Medical Male Circumcision in Zambia and Zimbabwe 
Devices for male circumcision (MC) are becoming available in 14 priority countries where MC is being implemented for HIV prevention. Understanding potential impact on demand for services is one important programmatic consideration because countries determine whether to scale up devices within MC programs.
A population-based survey measuring willingness to undergo MC, assuming availability of surgical MC and 3 devices, was conducted among 1250 uncircumcised men, ages 10–49 years in Zambia and 1000 uncircumcised men, ages 13–49 years in Zimbabwe. Simulated Test Market methodology was used to estimate incremental MC demand and the extent to which devices might be preferred over surgery, assuming availability of: surgical MC in both countries; the devices PrePex, ShangRing, and Unicirc in Zambia; and PrePex in Zimbabwe.
Modeled estimates indicate PrePex has the potential to provide an overall increase in MC demand ranging from an estimated 13%–50%, depending on country and WHO prequalification ages, replacing 11%–41% of surgical procedures. In Zambia, ShangRing could provide 8% overall increase, replacing 45% of surgical procedures, and Unicirc could provide 30% overall increase, replacing 85% of surgical procedures.
In both countries, devices have potential to increase overall demand for MC, assuming wide scale awareness and availability of circumcision by the devices. With consideration for age and country, PrePex may provide the greatest potential increase in demand, followed by Unicirc (measured in Zambia only) and ShangRing (also Zambia only). These results inform one program dimension for decision making on potential device introduction strategies; however, they must be considered within the broader programmatic context.
PMCID: PMC4936429  PMID: 27331597
voluntary medical male circumcision; circumcision; demand generation; devices; forecast; market research
5.  Voluntary Medical Male Circumcision: An HIV Prevention Priority for PEPFAR 
As the science demonstrating strong evidence for voluntary medical male circumcision (VMMC) for HIV prevention has evolved, the President’s Emergency Plan for AIDS Relief (PEPFAR) has collaborated with international agencies, donors, and partner country governments supporting VMMC programming. Mathematical models forecast that quickly reaching a large number of uncircumcised men with VMMC in strategically chosen populations may dramatically reduce community-level HIV incidence and save billions of dollars in HIV care and treatment costs. Because VMMC is a 1-time procedure that confers life-long partial protection against HIV, programs for adult men are vital short-term investments with long-term benefits. VMMC also provides a unique opportunity to reach boys and men with HIV testing and counseling services and referrals for other HIV services, including treatment. After formal recommendations by WHO in 2007, priority countries have pursued expansion of VMMC. More than 1 million males have received VMMC thus far, with the most notable successes coming from Kenya’s Nyanza Province. However, a myriad of necessary cultural, political, and ethical considerations have moderated the pace of overall success. Because many millions more uncircumcised men would benefit from VMMC services now, US President Barack Obama committed PEPFAR to provide 4.7 million males with VMMC by 2014. Innovative circumcision methods—such as medical devices that remove the foreskin without injected anesthesia and/or sutures—are being rigorously evaluated. Incorporation of safe innovations into surgical VMMC programs may provide the opportunity to reach more men more quickly with services and dramatically reduce HIV incidence for all.
PMCID: PMC3663585  PMID: 22797745
male circumcision; HIV prevention; PEPFAR
6.  Randomized Trial of Male Circumcision in HIV-infected Men: Effects on HIV Transmission to Female Partners, Rakai, Uganda 
Lancet  2009;374(9685):229-237.
A randomized trial of male circumcision (MC) was conducted among HIV-infected males to test the hypothesis that MC would reduce HIV transmission to female sexual partners.
This randomized, unblinded trial, conducted in Rakai District, Uganda, enrolled 922 uncircumcised, HIV-infected asymptomatic men aged 15–49 with CD4 counts ≥350. Men were randomly assigned to immediate circumcision (intervention) or circumcision delayed for 24 months (control). Concurrently enrolled HIV-negative female partners were followed up at 6, 12 and 24 months, to assess HIV acquisition by male MC assignment (primary outcome). An intention-to-treat analysis assessed women’s HIV acquisition using survival analysis and Cox proportional hazards modeling. The trial was registered in the Clinical Protocol Registration System (NCT00124878).
The trial was terminated for futility. Ninety three concurrently enrolled female partners of intervention arm men and 70 partners of control arm men provided follow up data. Cumulative probabilities of female HIV infection at 24 months were 21.7% (95% CI 12.7–33.4) in the intervention arm and 13.4% (95% CI 6.7–25.8) in the control arm (adjusted hazard ratio= 1.49, 95% CI 0.62–3.57, p = 0.368). At 6 months, intervention arm male-to-female transmission in couples who resumed intercourse ≥5 days prior to certified surgical wound healing was 27.8% (5/18), compared to 9.5% in couples who abstained longer post-surgically (6/63, p = 0.06) and 7.9% in control arm couples (5/63, p = 0.04)
Circumcision of HIV-infected men did not reduce HIV transmission to female partners over 24 months, and transmission risk may be increased with early post-surgical resumption of intercourse. Longer-term effects could not be assessed. Post surgical sexual abstinence and subsequent consistent condom are essential for HIV prevention.
PMCID: PMC2905212  PMID: 19616720
Male circumcision; randomized trial; HIV-infected men; female HIV acquisition; Uganda
7.  Daily Acyclovir Delays HIV-1 Disease Progression Among HIV-1/HSV-2 Dually-Infected Persons: A Randomized Trial 
Lancet  2010;375(9717):824-833.
Well-tolerated medications that slow HIV-1 disease progression and delay initiation of antiretroviral therapy (ART) are needed. Most HIV-1-infected persons are dually-infected with herpes simplex virus type 2 (HSV-2). Daily HSV-2 suppression reduces plasma HIV-1 levels, but whether HSV-2 suppression delays HIV-1 disease progression is unknown.
Within a randomized, placebo-controlled trial of HSV-2 suppressive therapy (acyclovir 400 mg orally bid) to decrease HIV-1 transmission, 3381 HSV-2/HIV-1 dually-infected heterosexual Africans who at enrollment had CD4 counts ≥250 cells/mm3 and were not taking ART were followed for up to 24 months. We evaluated the effect of acyclovir on HIV-1 disease progression, defined by a primary composite endpoint of first occurrence of CD4 count <200 cells/mm3, ART initiation, or non-trauma related death. As an exploratory analysis, we evaluated the endpoint of CD4 decline to <350 cells/mm3.
At enrollment, median CD4 was 462 cells/mm3 and median HIV-1 plasma RNA was 4.1 log10 copies/mL. Acyclovir reduced risk of HIV-1 disease progression: 284 participants on acyclovir versus 324 on placebo reached the primary endpoint (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.71–0.98, p=0.03). Among participants with CD4 counts ≥350 cells/mm3, acyclovir delayed risk of CD4 decline to <350 cells/mm3 (HR 0.81, 95% CI 0.71–0.93, p=0.002).
HSV-2 suppression with acyclovir reduced the risk of HIV-1 disease progression by 16% (95% CI 2–29%). The role of HSV-2 suppression in reducing HIV-1 disease progression prior to ART initiation warrants consideration ( #NCT00194519).
PMCID: PMC2877592  PMID: 20153888
HIV-1 disease progression; HIV-1 discordant couples; HSV-2; genital herpes; herpes suppression; acyclovir; randomized clinical trial
8.  Acyclovir and Transmission of HIV-1 from Persons Infected with HIV-1 and HSV-2 
The New England journal of medicine  2010;362(5):427-439.
Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1.
We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, ≥250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses.
A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P = 0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log10 copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2–positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed.
Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log10 copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. ( number, NCT00194519.)
PMCID: PMC2838503  PMID: 20089951
9.  The effects of male circumcision on female partner’s genital tract symptoms and vaginal infections in a randomized trial in Rakai, Uganda 
To assess effects of male circumcision on female genital symptoms, and vaginal infections.
HIV-negative men enrolled in a trial were randomized to immediate or delayed circumcision (control arm). Genital symptoms, BV and trichomonas were assessed in HIV-negative wives of married participants. Adjusted prevalence risk ratios (adjPRR) and 95% confidence intervals (95%CI) were assessed by multivariable log-binomial regression, intent-to-treat analyses.
783 wives of control and 825 wives of intervention arm men were comparable at enrollment. BV at enrollment was higher in control (38.3%) than intervention arm spouses (30.5%, p=0.001). At one year follow up, intervention arm wives reported lower rates of genital ulceration (adjPRR 0.78, 95%CI 0.63–0.97), but there were no differences in vaginal discharge or dysuria. The risk of trichomonas was reduced in intervention arm wives (adjPRR 0.52, 95%CI 0.05–0.98), as were the risks of any BV (adjPRR 0.60, 95%CI 0.38–0.94) and severe BV (PRR = 0.39, 95%CI 0.24–0.64).
Male circumcision reduces the risk of ulceration, trichomonas and BV in female partners.
PMCID: PMC2727852  PMID: 18976733
10.  In Global Health Research, Is It Legitimate To Stop Clinical Trials Early on Account of Their Opportunity Costs? 
PLoS Medicine  2009;6(6):e1000071.
Background to the debate
After the failure of three large clinical trials of vaginal microbicides, a Nature editorial stated that the microbicide field “requires a mechanism to help it make rational choices about the best candidates to move through trials” [1]. In this month's debate, James Lavery and colleagues propose a new mechanism, based on stopping trials early for “opportunity costs.” They argue that microbicide trial sites could have been saturated with trials of scientifically less advanced products, while newer, and potentially more promising, products were being developed. They propose a mechanism to reallocate resources invested in existing trials of older products that might be better invested in more scientifically advanced products that are awaiting clinical testing. But David Buchanan argues that the early stopping of trials for such opportunity costs would face insurmountable practical barriers, and would risk causing harm to the participants in the trial that was stopped.
This debate examines the ethics of reallocating resources invested in existing trials of older products into new trials of more scientifically advanced products.
PMCID: PMC2686164  PMID: 19513106
11.  The Safety of Adult Male Circumcision in HIV-Infected and Uninfected Men in Rakai, Uganda 
PLoS Medicine  2008;5(6):e116.
The objective of the study was to compare rates of adverse events (AEs) related to male circumcision (MC) in HIV-positive and HIV-negative men in order to provide guidance for MC programs that may provide services to HIV-infected and uninfected men.
Methods and Findings
A total of 2,326 HIV-negative and 420 HIV-positive men (World Health Organization [WHO] stage I or II and CD4 counts > 350 cells/mm3) were circumcised in two separate but procedurally identical trials of MC for HIV and/or sexually transmitted infection prevention in rural Rakai, Uganda. Participants were followed at 1–2 d and 5–9 d, and at 4–6 wk, to assess surgery-related AEs, wound healing, and resumption of intercourse. AE risks and wound healing were compared in HIV-positive and HIV-negative men. Adjusted odds ratios (AdjORs) were estimated by multiple logistic regression, adjusting for baseline characteristics and postoperative resumption of sex. At enrollment, HIV-positive men were older, more likely to be married, reported more sexual partners, less condom use, and higher rates of sexually transmitted disease symptoms than HIV-negative men. Risks of moderate or severe AEs were 3.1/100 and 3.5/100 in HIV-positive and HIV-negative participants, respectively (AdjOR 0.91, 95% confidence interval [CI] 0.47–1.74). Infections were the most common AEs (2.6/100 in HIV-positive versus 3.0/100 in HIV-negative men). Risks of other complications were similar in the two groups. The proportion with completed healing by 6 wk postsurgery was 92.7% in HIV-positive men and 95.8% in HIV-negative men (p = 0.007). AEs were more common in men who resumed intercourse before wound healing compared to those who waited (AdjOR 1.56, 95% CI 1.05–2.33).
Overall, the safety of MC was comparable in asymptomatic HIV-positive and HIV-negative men, although healing was somewhat slower among the HIV infected. All men should be strongly counseled to refrain from intercourse until full wound healing is achieved.
Trial registration:; for HIV-negative men, #NCT00047073 and for HIV-positive men, #NCT00047073.
Ron Gray and colleagues report on complications of circumcision in HIV-infected and HIV-uninfected men from two related trials in Uganda, finding increased risk with intercourse before wound healing.
Editors' Summary
Worldwide over 33 million people are thought to be living with HIV, and in the absence of a vaccine, preventing its spread is a major health issue. The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimate that 68% of 2.5 million new infections worldwide in 2007 took place in sub-Saharan Africa, where 76% of 2.1 million AIDS-related deaths also took place.
One of the principal means of person-to-person transmission of HIV is through sex without the protection of a condom. In parts of Africa, male circumcision is performed in infancy or childhood for religious or cultural reasons or is a traditional rite of passage that marks the transition from child to man. Three trials, in South Africa, Kenya, and Uganda, each found that circumcised men were around half as likely as uncircumcised men to contract HIV from HIV-positive female partners. After reviewing the results, WHO and UNAIDS issued joint advice that male circumcision should be promoted for preventing HIV infection in heterosexual men. As male circumcision does not provide complete protection against HIV infection, they advised that it should be promoted in addition to existing strategies of promoting condom use, abstinence, and a reduction in the number of sexual partners.
Why Was This Study Done?
Although earlier studies had shown that adult male circumcision, when performed in Africa under optimal conditions, is a safe procedure for HIV-negative men, it was not known whether it would also be a safe procedure for HIV-positive men. WHO guidelines recommend that HIV-positive men who request the procedure or have a medical need and no contraindications for it should be circumcised. Also, exclusion of HIV-positive men from circumcision programs may result in stigmatization of these men, and discourage participation by men who do not wish to be tested for HIV. Therefore, it is important to know whether the procedure is safe for HIV-positive men.
What Did the Researchers Do and Find?
The authors compared results from two separate clinical trials carried out with identical procedures in rural Rakai, Uganda. The first, which compared the effect of circumcision with no circumcision in HIV-negative men, was one of the three trials that persuaded the WHO and UNAIDS to promote male circumcision as an HIV prevention strategy. The second Rakai trial did the same comparison but in men who were HIV positive and without symptoms. In this present study, the authors used data from both trials to compare the likelihood of surgery-related complications following circumcision for HIV-negative and HIV-positive men.
The trials recruited men aged 15–49, who were randomly assigned to be circumcised either on enrollment or two years later and were followed up to monitor complications related to the procedure, such as infections, as well as wound healing and when the participant first had sex after the operation. Condom use was recorded at enrollment and six months after enrollment.
The researchers found that most complications were infrequent, mild, and comparable in both groups, with moderate-to-severe complications occurring in only 3%–4% of men in each group. However, delayed wound healing was more frequent in HIV-positive men. Complications were more likely among men who had sex before healing was complete; such men were more likely to be HIV-positive and/or married. Similarly, moderate or severe complications were more likely where men had symptoms of sexually transmitted disease at enrollment, although these were treated before surgery, and these men were more likely to be HIV-positive. Six months after enrollment, similar proportions of HIV-positive and HIV-negative men used condoms consistently, but HIV-positive men were more likely to report using condoms inconsistently than HIV-negative men. However, consistent use of a condom increased among the HIV-positive men compared to when they enrolled.
What Do these Findings Mean?
Circumcision in HIV-positive men without symptoms of AIDS has a low rate of complications, although healing is slower than in HIV-negative men. Because of the greater risk of complications if sex is resumed before full healing, both men and their women partners should be advised to have no sex for at least six weeks after the operation. A separately reported analysis from one of these studies found that women partners are more likely to become HIV infected by HIV-positive men who resume sex prior to complete wound healing. Therefore, for protection of both men and their female partners, it is essential to refrain from intercourse after circumcision until the wound has completely healed.
Because the study found no increased risk of surgical complications in HIV-positive men who undergo circumcision, it should not be necessary to screen men with no symptoms of HIV in future circumcision programs. This should reduce the complexity of implementing such programs and reduce any stigma resulting from exclusion, making it likely that more men will be willing to be circumcised. The rise in consistent condom use among HIV-positive men suggests that messages of safe sex are reaching an important target group and changing their behavior, and that circumcision does not make men less likely to use a condom.
The authors also noted that the rates of complications they observed were low compared with those following traditional circumcision procedures. Others have found that circumcision carried out under unsafe conditions has a high rate of complications. The authors of this study comment that the resources and standards of surgery during the trial represented best practice and that to attain similarly low rates of complications—and the confidence of men in the safety of the procedure—there is a need to ensure sufficient resources and high standards of training.
Additional Information.
Please access these Web sites via the online version of this summary at
WHO and the UNAIDS issued a joint report recommending male circumcision for HIV prevention and another on the HIV epidemic worldwide in December 2007
An information pack here on male circumcision and HIV prevention has also been developed jointly by WHO/UNAIDS, the United Nations International Children's Emergency Fund (UNICEF), the United Nations Population Fund (UNFPA), and the World Bank
The University of California San Francisco's HIV InSite provides information on HIV prevention, treatment, and policy
AEGIS is the world's largest searchable database on HIV and AIDS
The National AIDS Trust provides information on HIV prevention
PMCID: PMC2408615  PMID: 18532873
12.  Tenofovir Disoproxil Fumarate for Prevention of HIV Infection in Women: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Trial 
PLoS Clinical Trials  2007;2(5):e27.
The objective of this trial was to investigate the safety and preliminary effectiveness of a daily dose of 300 mg of tenofovir disoproxil fumarate (TDF) versus placebo in preventing HIV infection in women.
This was a phase 2, randomized, double-blind, placebo-controlled trial.
The study was conducted between June 2004 and March 2006 in Tema, Ghana; Douala, Cameroon; and Ibadan, Nigeria.
We enrolled 936 HIV-negative women at high risk of HIV infection into this study.
Participants were randomized 1:1 to once daily use of 300 mg of TDF or placebo.
Outcome measures:
The primary safety endpoints were grade 2 or higher serum creatinine elevations (>2.0 mg/dl) for renal function, grade 3 or 4 aspartate aminotransferase or alanine aminotransferase elevations (>170 U/l) for hepatic function, and grade 3 or 4 phosphorus abnormalities (<1.5 mg/dl). The effectiveness endpoint was infection with HIV-1 or HIV-2.
Study participants contributed 428 person-years of laboratory testing to the primary safety analysis. No significant differences emerged between treatment groups in clinical or laboratory safety outcomes. Study participants contributed 476 person-years of HIV testing to the primary effectiveness analysis, during which time eight seroconversions occurred. Two were diagnosed in participants randomized to TDF (0.86 per 100 person-years) and six in participants receiving placebo (2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% confidence interval = 0.03–1.93), which did not achieve statistical significance. Owing to premature closures of the Cameroon and Nigeria study sites, the planned person-years of follow-up and study power could not be achieved.
Daily oral use of TDF in HIV-uninfected women was not associated with increased clinical or laboratory adverse events. Effectiveness could not be conclusively evaluated because of the small number of HIV infections observed during the study.
Editorial Commentary
Background: The World Health Organization has estimated that in 2006 around 4.3 million people were newly infected with HIV. Infection rates seem to be increasing in some countries, and there is an urgent need to find safe and effective ways of preventing HIV from being transmitted from one person to another. Many strategies for the prevention of HIV transmission between adults, such as use of condoms or changes to behavior, are not completely reliable, and women, in particular, may not always be able to negotiate condom use. Additional strategies for reducing the risk of HIV transmission are needed. One of these strategies is called “pre-exposure prophylaxis.” This strategy involves individuals who are at high risk of becoming infected with HIV taking antiviral drugs to prevent HIV infection. One particular drug, tenofovir disoproxil fumarate, is currently approved as a treatment for HIV infection, and is also being investigated as a strong candidate for pre-exposure prophylaxis. The research presented here reports on results of a trial carried out at three different sites in Ghana, Cameroon, and Nigeria. In the trial, 936 women who were not infected with HIV but who were at high risk of becoming infected, were randomized to take tenofovir tablets daily or, alternatively, placebo tablets. The researchers planned to follow up with the women for 12 months, and the primary analysis for efficacy would focus on a comparison of the rate of new HIV infections between the two arms of the trial. Primary safety analyses included specific laboratory tests carried out on blood samples that might point to abnormalities in liver or kidney function. Safety data were also collected throughout the trial, and health problems that arose were classified as adverse events or serious adverse events.
What this trial shows: Unfortunately, this trial was not completed as planned. Two sites (Nigeria and Cameroon) were closed either before the planned number of participants had been recruited or before all participants had completed full follow-up. Therefore, not enough data were available from this trial to determine whether tenofovir reduced the risk of HIV infection. Only two sites contributed data for the primary safety analyses, which looked at liver and kidney function. The researchers did not see any statistically significant differences in these safety endpoints between participants taking tenofovir and those taking placebo. There were also no statistically significant differences between the treatment groups in the number of adverse events. The main efficacy analysis found two new HIV infections in the tenofovir group and six in the placebo group. Because only eight effectiveness endpoints were observed during this study, the difference in HIV incidence between these groups was not statistically significant.
Strengths and limitations: A strength of this trial is that it was correctly designed to address the original objectives of the study, involving appropriate concealment of randomization and blinding of participants and study staff to treatment assignment. The main limitation of this study was the closure of two study sites, which meant that the study did not have sufficient power to assess differences between trial arms in the primary efficacy analysis.
Contribution to the evidence: At the time this trial was completed, there was no other evidence from randomized studies that evaluated antiretroviral drugs for prevention of HIV infection. This trial cannot, however, definitively address whether tenofovir reduces the risk of HIV infection among at-risk women or not. Ongoing and future trials are essential in order to answer this question. The trial reported here provides important data on the safety of daily tenofovir among high-risk HIV-uninfected women; the safety data are encouraging and suggest that tenofovir use is not associated with increased adverse events as compared to placebo.
PMCID: PMC1876601  PMID: 17525796
13.  Bioterrorism-related Inhalational Anthrax in an Elderly Woman, Connecticut, 2001 
Emerging Infectious Diseases  2003;9(6):681-688.
On November 20, 2001, inhalational anthrax was confirmed in an elderly woman from rural Connecticut. To determine her exposure source, we conducted an extensive epidemiologic, environmental, and laboratory investigation. Molecular subtyping showed that her isolate was indistinguishable from isolates associated with intentionally contaminated letters. No samples from her home or community yielded Bacillus anthracis, and she received no first-class letters from facilities known to have processed intentionally contaminated letters. Environmental sampling in the regional Connecticut postal facility yielded B. anthracis spores from 4 (31%) of 13 sorting machines. One extensively contaminated machine primarily processes bulk mail. A second machine that does final sorting of bulk mail for her zip code yielded B. anthracis on the column of bins for her carrier route. The evidence suggests she was exposed through a cross-contaminated bulk mail letter. Such cross-contamination of letters and postal facilities has implications for managing the response to future B. anthracis–contaminated mailings.
PMCID: PMC3000148  PMID: 12781007
Bacillus anthracis; inhalational anthrax; bioterrorism; postal facilities; research
14.  Use of DNA Fingerprinting To Investigate a Multiyear, Multistate Tuberculosis Outbreak 
Emerging Infectious Diseases  2002;8(11):1152-1156.
In 1998–1999, the Baltimore TB control program detected a cluster of 21 tuberculosis (TB) cases. Patients reported frequent travel to various East Coast cities. An investigation was conducted to determine whether transmission of the same Mycobacterium tuberculosis strain was occurring in these other localities. A collaborative investigation among federal, state, and local TB controllers included TB record reviews, interviews of patients, and restriction fragment length polymorphism (RFLP) analysis of selected M. tuberculosis isolates from diagnosed TB patients in several cities in 1996–2001. A national TB genotyping database was searched for RFLP patterns that matched the outbreak pattern. Eighteen additional outbreak-related cases were detected outside of Baltimore—the earliest diagnosed in New Jersey in 1996, and the most recent in New York City in late 2001. The outbreak demonstrates the need for strategies to detect links among patients diagnosed with TB across multiple TB control jurisdictions.
PMCID: PMC2738549
tuberculosis; Mycobacterium tuberculosis; outbreaks; DNA fingerprinting; transgender
15.  Antimicrobial Postexposure Prophylaxis for Anthrax: Adverse Events and Adherence 
Emerging Infectious Diseases  2002;8(10):1124-1132.
We collected data during postexposure antimicrobial prophylaxis campaigns and from a prophylaxis program evaluation 60 days after start of antimicrobial prophylaxis involving persons from six U.S. sites where Bacillus anthracis exposures occurred. Adverse events associated with antimicrobial prophylaxis to prevent anthrax were commonly reported, but hospitalizations and serious adverse events as defined by Food and Drug Administration criteria were rare. Overall adherence during 60 days of antimicrobial prophylaxis was poor (44%), ranging from 21% of persons exposed in the Morgan postal facility in New York City to 64% of persons exposed at the Brentwood postal facility in Washington, D.C. Adherence was highest among participants in an investigational new drug protocol to receive additional antibiotics with or without anthrax vaccine—a likely surrogate for anthrax risk perception. Adherence of <60 days was not consistently associated with adverse events.
PMCID: PMC2730317  PMID: 12396927
Anthrax; Bacillus anthracis; antimicrobial prophylaxis; adverse events; adherence
16.  Anthrax Postexposure Prophylaxis in Postal Workers, Connecticut, 2001 
Emerging Infectious Diseases  2002;8(10):1133-1137.
After inhalational anthrax was diagnosed in a Connecticut woman on November 20, 2001, postexposure prophylaxis was recommended for postal workers at the regional mail facility serving the patient’s area. Although environmental testing at the facility yielded negative results, subsequent testing confirmed the presence of Bacillus anthracis. We distributed questionnaires to 100 randomly selected postal workers within 20 days of initial prophylaxis. Ninety-four workers obtained antibiotics, 68 of whom started postexposure prophylaxis and 21 discontinued. Postal workers who stopped or never started taking prophylaxis cited as reasons disbelief regarding anthrax exposure, problems with adverse events, and initial reports of negative cultures. Postal workers with adverse events reported predominant symptoms of gastrointestinal distress and headache. The influence of these concerns on adherence suggests that communication about risks of acquiring anthrax, education about adverse events, and careful management of adverse events are essential elements in increasing adherence.
PMCID: PMC2730305  PMID: 12396928
Anthrax; Bacillus anthracis; prophylaxis; adverse effects; ciprofloxacin; doxycycline; patient noncompliance; Connecticut
17.  Bioterrorism-Related Anthrax Surveillance, Connecticut, September–December, 2001 
Emerging Infectious Diseases  2002;8(10):1078-1082.
On November 19, 2001, a case of inhalational anthrax was identified in a 94-year-old Connecticut woman, who later died. We conducted intensive surveillance for additional anthrax cases, which included collecting data from hospitals, emergency departments, private practitioners, death certificates, postal facilities, veterinarians, and the state medical examiner. No additional cases of anthrax were identified. The absence of additional anthrax cases argued against an intentional environmental release of Bacillus anthracis in Connecticut and suggested that, if the source of anthrax had been cross-contaminated mail, the risk for anthrax in this setting was very low. This surveillance system provides a model that can be adapted for use in similar emergency settings.
PMCID: PMC2730303  PMID: 12396919
18.  Antiretroviral Therapy in Prevention of HIV and TB: Update on Current Research Efforts 
Current HIV Research  2011;9(6):446-469.
There is considerable scientific evidence supporting the use of antiretroviral therapy (ART) in prevention of human immunodeficiency virus (HIV) and tuberculosis (TB) infections. The complex nature of the HIV and TB prevention responses, resource constraints, remaining questions about cost and feasibility, and the need to use a solid evidence base to make policy decisions, and the implementation challenges to translating trial data to operational settings require a well-organised and coordinated response to research in this area. To this end, we aimed to catalogue the ongoing and planned research activities that evaluate the impact of ART plus other interventions on HIV- and/or TB-related morbidity, mortality, risk behaviour, HIV incidence and transmission. Using a limited search methodology, 50 projects were identified examining ART as prevention, representing 5 regions and 52 countries with a global distribution. There are 24 randomised controlled clinical trials with at least 12 large randomised individual or community cluster trials in resource-constrained settings that are in the planning or early implementation stages. There is considerable heterogeneity between studies in terms of methodology, interventions and geographical location. While the identified studies will undoubtedly advance our understanding of the efficacy and effectiveness of ART for prevention, some key questions may remain unanswered or only partially answered. The large number and wide variety of research projects emphasise the importance of this research issue and clearly demonstrate the potential for synergies, partnerships and coordination across funding agencies.
PMCID: PMC3531820  PMID: 21999779
HAART; highly active antiretroviral therapy; HIV prevention; randomised controlled trials; research activities; tuberculosis prevention.

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