Allan R. Ronald

Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women

BACKGROUND Antiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations. METHODS We conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens--once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo--and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services. RESULTS We enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study. CONCLUSIONS Oral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.).

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

BACKGROUND 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. METHODS 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, > 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. RESULTS 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 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. CONCLUSIONS Daily 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.)

Laboratory Medicine in Africa: A Barrier to Effective Health Care

Providing health care in sub-Saharan Africa is a complex problem. Recent reports call for more resources to assist in the prevention and treatment of infectious diseases that affect this population, but policy makers, clinicians, and the public frequently fail to understand that diagnosis is essential to the prevention and treatment of disease. Access to reliable diagnostic testing is severely limited in this region, and misdiagnosis commonly occurs. Understandably, allocation of resources to diagnostic laboratory testing has not been a priority for resource-limited health care systems, but unreliable and inaccurate laboratory diagnostic testing leads to unnecessary expenditures in a region already plagued by resource shortages, promotes the perception that laboratory testing is unhelpful, and compromises patient care. We explore the barriers to implementing consistent testing within this region and illustrate the need for a more comprehensive approach to the diagnosis of infectious diseases, with an emphasis on making laboratory testing a higher priority.

AIDS virus infection in Nairobi prostitutes: spread of the epidemic to East Africa

The acquired immunodeficiency syndrome (AIDS) is epidemic in Central Africa. To determine the prevalence of AIDS virus infection in East Africa, we studied 90 female prostitutes, 40 men treated at a clinic for sexually transmitted diseases, and 42 medical personnel in Nairobi, Kenya. Antibody to human T-cell lymphotropic virus Type III (HTLV-III) was detected in the serum of 66 percent of prostitutes of low socioeconomic status, 31 percent of prostitutes of higher socioeconomic status, 8 percent of the clinic patients, and 2 percent of the medical personnel. The presence of the antibody was associated with both immunologic and clinical abnormalities. The mean T-cell helper/suppressor ratio was 0.92 in seropositive prostitutes and 1.82 in seronegative prostitutes (P less than 0.0001). Generalized lymphadenopathy was present in 54 percent of seropositive prostitutes and 10 percent of seronegative prostitutes (P less than 0.0001). No constitutional symptoms, opportunistic infections, or cases of Kaposis sarcoma were present. Our results indicate that the epidemic of AIDS virus infection has, unfortunately, spread extensively among urban prostitutes in Nairobi, Kenya. Sexual exposure to men from Central Africa was significantly associated with HTLV-III antibody among prostitutes, suggesting transcontinental spread of the epidemic.

Genital ulceration as a risk factor for human immunodeficiency virus infection

Among 115 heterosexual men who presented with genital ulcers to a sexually transmitted disease clinic in Nairobi, Kenya, the prevalence of serum antibody to HIV was 16.5%. A past history of genital ulcers was reported by 12 (63%) of 19 men with antibody to HIV versus 30 (31%) of 96 without antibody (P = 0.008). HIV infection was also positively associated with lack of circumcision, but was not associated with the etiology of the current genital ulcer. Logistic regression analysis (adjusted for age, number of recent sex partners, recent prostitute contact, circumcision, tribal ethnic identity, past history of urethritis, and current diagnoses) confirmed only the association between prior history of genital ulcer disease and HIV infection; (P = 0.04, odds ratio 2.35, 95% confidence limits, 1.01-5.47). The incidence of genital ulcers, particularly chancroid, is much higher in parts of Africa than in Europe or North America. This may contribute to the increased risk of heterosexual transmission of HIV in Africa. Aggressive control of chancroid and syphilis may offer one very feasible approach to reducing transmission of HIV in this region.

Outcomes of Cryptococcal Meningitis in Uganda Before and After the Availability of Highly Active Antiretroviral Therapy

BACKGROUND Cryptococcal meningitis (CM) is the proximate cause of death in 20%-30% of persons with acquired immunodeficiency syndrome in Africa. METHODS Two prospective, observational cohorts enrolled human immunodeficiency virus (HIV)-infected, antiretroviral-naive persons with CM in Kampala, Uganda. The first cohort was enrolled in 2001-2002 (n = 92), prior to the availability of highly active antiretroviral therapy (HAART), and the second was enrolled in 2006-2007 (n = 44), when HAART was available. RESULTS Ugandans presented with prolonged CM symptoms (median duration, 14 days; interquartile range, 7-21 days). The 14-day survival rates were 49% in 2001-2002 and 80% in 2006 (P < .001). HAART was started 35 +/- 13 days after CM diagnosis and does not explain the improved 14-day survival rate in 2006. In 2006-2007, the survival rate continued to decrease after hospitalization, with only 55% surviving to initiate HAART as an outpatient. Probable cryptococcal-related immune reconstitution inflammatory syndrome occurred in 42% of patients, with 4 deaths. At 6 months after CM diagnosis, 18 persons (41%) were alive and receiving HAART in 2007. The median cerebral spinal fluid (CSF) opening pressure was 330 mm H(2)O; 81% of patients had elevated pressure (>200 mm H(2)O). Only 5 patients consented to therapeutic lumbar puncture. There was a trend for higher mortality for pressures >250 mm H(2)O (odds ratio [OR], 2.1; 95% confidence interval [CI], 0.9-5.2; P = .09). Initial CSF WBC counts of <5 cells/mL were associated with failure of CSF sterilization (OR, 17.3; 95% CI, 3.1-94.3; P < .001), and protein levels <35 mg/dL were associated with higher mortality (OR, 2.0; 95% CI, 1.2-3.3; P = .007). CONCLUSIONS Significant CM-associated mortality persists, despite the administration of amphotericin B and HIV therapy, because of the high mortality rate before receipt of HAART and because of immune reconstitution inflammatory syndrome-related complications after HAART initiation. Approaches to increase acceptance of therapeutic lumbar punctures are needed.

Rapid tests for sexually transmitted infections (STIs): the way forward

In the developing world, laboratory services for sexually transmitted infections (STIs) are either not available, or where limited services are available, patients may not be able to pay for or physically access those services. Despite the existence of national policy for antenatal screening to prevent congenital syphilis and substantial evidence that antenatal screening is cost-effective, implementation of syphilis screening programmes remains unacceptably low because of lack of screening tools that can be used in primary health care settings. The World Health Organization Sexually Transmitted Diseases Diagnostics Initiative (SDI) has developed the ASSURED criteria as a benchmark to decide if tests address disease control needs: Affordable, Sensitive, Specific, User-friendly, Rapid and robust, Equipment-free and Deliverable to end-users. Rapid syphilis tests that can be used with whole blood approach the ASSURED criteria and can now be deployed in areas where no previous screening has been possible. Although rapid tests for chlamydia and gonorrhoea lack sensitivity, more tests are in development. The way forward for STI diagnostics requires a continuing quest for ASSURED tests, the development of a road map for test introduction, sustainable programmes for quality assurance, and the creation of a robust infrastructure linked to HIV prevention that ensures sustainability of STI control efforts that includes viral STIs.

Predictors of long-term viral failure among ugandan children and adults treated with antiretroviral therapy.

Background:HIV RNA viral load testing is costly and is generally unavailable in resource-limited settings. We identified predictors of viral failure and documented genotypic mutations in a subset of patients with viral failure after 12 months on antiretroviral therapy (ART). Methods:From April 2004 to June 2005, consecutive treatment-naive patients beginning ART at a university clinic in Uganda were enrolled. Clinical information, CD4 cell count, and HIV RNA level were collected at baseline and every 3 to 6 months. Independent predictors of viral failure were identified using multivariate logistic regression. Genotypic drug resistance for 8 patients with viral failure at 12 months was measured at baseline and at 6 and 12 months. Results:Five hundred twenty-six adults and 250 children (0 to 18 years of age) were started on first-line ART regimens and followed for 12 months. Outcomes could not be assessed in 13% of patients (79 died and 21 were withdrawn). Children were almost twice as likely to have viral failure compared with adults (26% vs. 14%; P = 0.0001). In adults, the sole independent predictor of viral failure was treatment with stavudine (d4T)/lamivudine (3TC)/nevirapine (NVP) versus zidovudine (ZDV)/3TC/efavirenz (EFV) (odds ratio [OR] = 2.59, 95% confidence interval [CI]: 1.20 to 5.59). In children, independent predictors of viral failure included male gender (OR = 2.44, 95% CI: 1.20 to 4.93), baseline CD4% <5 (OR = 2.69, 95% CI: 1.28 to 5.63), and treatment with d4T/3TC/NVP versus ZDV/3TC/EFV (OR = 2.46, 95% CI: 1.23 to 4.90). All 8 patients with viral breakthrough and genotypic drug resistance results had nonnucleoside reverse transcriptase inhibitor (NNRTI)- and 3TC-associated mutations. Conclusions:These data demonstrate the effectiveness of ART in a low-resource setting. Children and patients of all ages taking the d4T/3TC/NVP regimen were more likely to have viral failure. Our data suggest that viral failure occurring 6 months or more after the start of ART regimens commonly used in Uganda is likely to be associated with NNRTI- and 3TC-resistant virus.

Urinary tract infection in adults: research priorities and strategies

Waning interest in urinary tract infection (UTI) research has limited clinical advances during the past two decades. Although care has improved for some specific UTI syndromes, there is limited evidence for most of the decisions made each day in the management of these infections. Additional clinical research is necessary to improve UTI prevention and care strategies.

How Long Should Catheter-Acquired Urinary Tract Infection in Women Be Treated?: A Randomized Controlled Study

OBJECTIVE To determine the optimal management of catheter-acquired bacteriuria after short-term catheter use in women. PATIENTS Asymptomatic patients (119) with catheter-acquired bacteriuria were randomly assigned to receive no therapy, a single dose (320-1600 mg) of therapy with trimethoprim-sulfamethoxazole, or 10 days (160-800 mg twice daily) of therapy. Thirty-two patients with lower tract symptoms alone received a single dose or 10 days of therapy, and 10 patients with upper tract symptoms or signs received 10 days of therapy. MAIN RESULTS The mean and median durations of catheter use were 6 and 4 days, respectively. Bacteriuria resolved within 14 days without therapy in 15 of 42 (36%; 95% CI, 21% to 51%) asymptomatic patients. Seven of the remaining patients developed symptoms. Single-dose therapy resolved infection in 30 of 37 patients (81%; CI, 68% to 94%); 10 days of therapy resolved infection in 26 of 33 (79%; CI, 65% to 93%). For patients with lower tract symptoms alone, resolution rates with single-dose therapy or 10 days of therapy were similar (11 of 14 [79%] and 13 of 16 [81%], respectively). Ten days of therapy resolved infection in 6 of 9 (67%) patients with upper tract symptoms. Infection was resolved more often in women who were less than or equal to 65 years than in older women (62 of 70 [89%] versus 24 of 39 [62%]; P less than 0.001). Bacteriuria resolved spontaneously more frequently in younger (14 of 19 [74%] compared with 1 of 23 older women [4%]; P less than 0.001). Single-dose therapy resolved infection in 31 of 33 (94%) patients who were less than or equal to 65 years. CONCLUSIONS Asymptomatic bacteriuria after short-term catheter use frequently becomes symptomatic and should be treated. For asymptomatic patients and patients with lower tract symptoms alone, single-dose therapy was as effective as 10 days of therapy; it was very effective in women who were less than or equal to 65 years. Bacteriuria resolved spontaneously within 14 days after catheter removal more commonly in women who were less than or equal to 65 years and both types of therapy were less effective in older women.