Renee Ridzon

Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2.

BACKGROUNDnMost 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.nnnMETHODSnWe 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, > or = 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.nnnRESULTSnA 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 log(10) 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.nnnCONCLUSIONSnDaily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)

Circumcision in HIV-infected men and its effect on HIV transmission to female partners in Rakai, Uganda: a randomised controlled trial

BACKGROUNDnObservational studies have reported an association between male circumcision and reduced risk of HIV infection in female partners. We assessed whether circumcision in HIV-infected men would reduce transmission of the virus to female sexual partners.nnnMETHODSn922 uncircumcised, HIV-infected, asymptomatic men aged 15-49 years with CD4-cell counts 350 cells per microL or more were enrolled in this unblinded, randomised controlled trial in Rakai District, Uganda. Men were randomly assigned by computer-generated randomisation sequence to receive immediate circumcision (intervention; n=474) or circumcision delayed for 24 months (control; n=448). HIV-uninfected female partners of the randomised men were concurrently enrolled (intervention, n=93; control, n=70) and followed up at 6, 12, and 24 months, to assess HIV acquisition by male treatment assignment (primary outcome). A modified intention-to-treat (ITT) analysis, which included all concurrently enrolled couples in which the female partner had at least one follow-up visit over 24 months, assessed female HIV acquisition by use of survival analysis and Cox proportional hazards modelling. This trial is registered with ClinicalTrials.gov, number NCT00124878.nnnFINDINGSnThe trial was stopped early because of futility. 92 couples in the intervention group and 67 couples in the control group were included in the modified ITT analysis. 17 (18%) women in the intervention group and eight (12%) women in the control group acquired HIV during follow-up (p=0.36). Cumulative probabilities of female HIV infection at 24 months were 21.7% (95% CI 12.7-33.4) in the intervention group and 13.4% (6.7-25.8) in the control group (adjusted hazard ratio 1.49, 95% CI 0.62-3.57; p=0.368).nnnINTERPRETATIONnCircumcision of HIV-infected men did not reduce HIV transmission to female partners over 24 months; longer-term effects could not be assessed. Condom use after male circumcision is essential for HIV prevention.nnnFUNDINGnBill & Melinda Gates Foundation with additional laboratory and training support from the National Institutes of Health and the Fogarty International Center.

Tenofovir Disoproxil Fumarate for Prevention of HIV Infection in Women: A Phase 2, Double- Blind, Randomized, Placebo-Controlled Trial

Objectives: 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. Design: This was a phase 2, randomized, double-blind, placebo-controlled trial. Setting: The study was conducted between June 2004 and March 2006 in Tema, Ghana; Douala, Cameroon; and Ibadan, Nigeria. Participants: We enrolled 936 HIV-negative women at high risk of HIV infection into this study. Intervention: 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. Results: 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. Conclusion: 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.

The effects of male circumcision on female partners' genital tract symptoms and vaginal infections in a randomized trial in Rakai, Uganda.

OBJECTIVEnThe objective of the study was to assess effects of male circumcision on female genital symptoms and vaginal infections.nnnSTUDY DESIGNnHuman immunodeficiency virus (HIV)-negative men enrolled in a trial were randomized to immediate or delayed circumcision (control arm). Genital symptoms, bacterial vaginosis (BV), and trichomonas were assessed in HIV-negative wives of married participants. Adjusted prevalence risk ratios (adjPRR) and 95% confidence intervals (CIs) were assessed by multivariable log-binomial regression, intent-to-treat analyses.nnnRESULTSnA total of 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 = .001). At 1 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 (prevalence risk ratios, 0.39; 95% CI, 0.24-0.64).nnnCONCLUSIONnMale circumcision reduces the risk of ulceration, trichomonas, and BV in female partners.

Extensive Transmission of Mycobacterium tuberculosis from a Child

BACKGROUND AND METHODSnYoung children rarely transmit tuberculosis. In July 1998, infectious tuberculosis was identified in a nine-year-old boy in North Dakota who was screened because extrapulmonary tuberculosis had been diagnosed in his female guardian. The child, who had come from the Republic of the Marshall Islands in 1996, had bilateral cavitary tuberculosis. Because he was the only known possible source for his female guardians tuberculosis, an investigation of the childs contacts was undertaken. We identified family, school, day-care, and other social contacts and notified these people of their exposure. We asked the contacts to complete a questionnaire and performed tuberculin skin tests.nnnRESULTSnOf the 276 contacts of the child whom we tested, 56 (20 percent) had a positive tuberculin skin test (induration of at least 10 mm), including 3 of the childs 4 household members, 16 of his 24 classroom contacts, 10 of 32 school-bus riders, and 9 of 61 day-care contacts. A total of 118 persons received preventive therapy, including 56 young children who were prescribed preventive therapy until skin tests performed at least 12 weeks after exposure were negative. The one additional case identified was in the twin brother of the nine-year-old patient. The twin was not considered infectious on the basis of a sputum smear that was negative on microscopical examination.nnnCONCLUSIONSnThis investigation showed that a young child can transmit Mycobacterium tuberculosis to a large number of contacts. Children with tuberculosis, especially cavitary or laryngeal tuberculosis, should be considered potentially infectious, and screening of their contacts for infection with M. tuberculosis or active tuberculosis may be required.

Simultaneous Transmission of Human Immunodeficiency Virus and Hepatitis C Virus from a Needle-Stick Injury

Human immunodeficiency virus type 1 (HIV) and hepatitis C virus (HCV) are blood-borne viruses that pose occupational hazards to health care workers exposed to the blood of infected patients. As of June 1996, 51 documented and 108 possible cases of occupationally acquired HIV infection had been reported to the Centers for Disease Control and Prevention (CDC).1 The estimated risk of acquiring HIV infection after percutaneous exposure to blood from an HIV-infected patient is 0.3 percent.2 Recommendations for follow-up after occupational exposure to HIV-infected blood include HIV-antibody testing at the time of exposure and periodically for at least six months thereafter. .xa0.xa0.

Daily aciclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial

Background nWell-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.BACKGROUNDnMost people infected with HIV-1 are dually infected with herpes simplex virus type 2. Daily suppression of this herpes virus reduces plasma HIV-1 concentrations, but whether it delays HIV-1 disease progression is unknown. We investigated the effect of acyclovir on HIV-1 progression.nnnMETHODSnIn a trial with 14 sites in southern Africa and east Africa, 3381 heterosexual people who were dually infected with herpes simplex virus type 2 and HIV-1 were randomly assigned in a 1:1 ratio to acyclovir 400 mg orally twice daily or placebo, and were followed up for up to 24 months. Eligible participants had CD4 cell counts of 250 cells per mL or higher and were not taking antiretroviral therapy. We used block randomisation, and patients and investigators were masked to treatment allocation. Effect of acyclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts of fewer than 200 cells per microL, antiretroviral therapy initiation, or non-trauma related death. As an exploratory analysis, we assessed the endpoint of CD4 falling to <350 cells per microL. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00194519.nnnFINDINGSnAt enrollment, the median CD4 cell count was 462 cells per microL and median HIV-1 plasma RNA was 4.1 log(10) copies per microL. Acyclovir reduced risk of HIV-1 disease progression by 16%; 284 participants assigned acyclovir versus 324 assigned placebo reached the primary endpoint (hazard ratio [HR] 0.84, 95% CI 0.71-0.98, p=0.03). In those with CD4 counts >or=350 cells per microL, aciclovir delayed risk of CD4 cell counts falling to <350 cells per microL by 19% (0.81, 0.71-0.93, p=0.002)nnnINTERPRETATIONnThe role of suppression of herpes simplex virus type 2 in reduction of HIV-1 disease progression before initiation of antiretroviral therapy warrants consideration.nnnFUNDINGnBill & Melinda Gates Foundation.

The Safety of adult male circumcision in HIV-infected and uninfected men in Rakai, Uganda

Background 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). Conclusions 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: http://www.ClinicalTrials.gov; for HIV-negative men, #NCT00047073 and for HIV-positive men, #NCT00047073.

Antiretroviral Therapy in Prevention of HIV and TB: Update on Current Research Efforts

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.

Outbreak of drug-resistant tuberculosis with second-generation transmission in a high school in California

BACKGROUNDnIn spring 1993, four students in a high school were diagnosed with tuberculosis resistant to isoniazid, streptomycin, and ethionamide.nnnMETHODSnTo investigate potential transmission of drug-resistant tuberculosis, a retrospective cohort study with case investigation and screening by tuberculin skin tests and symptom checks was conducted in a high school of approximately 1400 students. Current and graduated high-school students were included in the investigation. DNA fingerprinting of available isolates was performed.nnnRESULTSnEighteen students with active tuberculosis were identified. Through epidemiologic and laboratory investigation, 13 cases were linked; 8 entered 12th grade in fall 1993; 9 of 13 had positive cultures for Mycobacterium tuberculosis with isoniazid, streptomycin, and ethionamide resistance, and all 8 available isolates had identical DNA fingerprints. No staff member had tuberculosis. One student remained infectious for 29 months, from January 1991 to June 1993, and was the source case for the outbreak. Another student was infectious for 5 months before diagnosis in May 1993 and was a treatment failure in February 1994 with development of rifampin and ethambutol resistance in addition to isoniazid, streptomycin, and ethionamide. In the fall 1993 screening, 292 of 1263 (23%) students tested had a positive tuberculin skin test. Risk of infection was highest among 12th graders and classroom contacts of the two students with prolonged infectiousness. An additional 94 of 928 (10%) students tested in spring 1994 had a positive tuberculin skin test; 22 were classroom contacts of the student with treatment failure and 21 of these had documented tuberculin skin test conversions.nnnCONCLUSIONnExtensive transmission of drug-resistant tuberculosis was documented in this high school, along with missed opportunities for prevention and control of this outbreak. Prompt identification of tuberculosis cases and timely interventions should help reduce this public health problem.