Day: 11/23/2010

Oral Preexposure Prophylaxis for HIV

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Despite the growing global access to life-extending antiretroviral drugs for the more than 33 million persons living with human immunodeficiency virus (HIV) infection, approximately 7000 new infections occur daily. This alarming number speaks to the critical need for effective approaches to HIV prevention.1 Early approaches to prevention were limited to the consistent use of barrier methods during sex,2 a reduction in the prevalence of HIV in the blood supply, behavior modification, postexposure prophylaxis, and awareness of HIV-infection status. Antiretroviral drugs that were provided to pregnant women with HIV infection were shown to dramatically reduce the risk of perinatal transmission,3 with added protection to treated breast-fed infants of HIV-infected mothers.4 A single study suggested that treatment of intercurrent sexually transmitted infections could decrease the susceptibility to HIV.5

However, continually impressive advances in the effectiveness of potent antiretroviral therapy to treat chronic HIV infection from 1995 to the present were not matched with concomitant improvements in methods for HIV prevention until relatively recently. For quite some time, the HIV-prevention quiver held precious few arrows. This began to change in the period from 2005 through 2007, when studies showed that adult male circumcision, vaccination, or the use of a vaginal microbicide could variably reduce the risk of HIV infection.6-10 However, the need for more and better preventive treatments remains.

In this issue of the Journal, Grant and colleagues11 report evidence that antiretroviral medications, specifically the combination of emtricitabine and tenofovir disoproxil fumarate (FTC–TDF), taken orally on a daily basis by men and transgender women (born male) who have sex with men, can provide partial protection from HIV infection. The trial, called the Preexposure Prophylaxis Initiative (iPrEx) study (ClinicalTrials.gov number, NCT00458393), was a placebo-controlled, double-blind, randomized trial involving 2499 subjects in the Americas, South Africa, and Thailand. Of the 100 incident infections, 64 occurred in the placebo group and 36 in the FTC–TDF group, for an estimated efficacy of 44% with a 95% confidence interval of 15 to 63. In the FTC–TDF group, the study drug was pharmacologically detected in 51% of subjects who remained free of HIV infection but in only 9% of those who became infected. Thus, exposure to FTC–TDF was associated with a reduction in HIV acquisition, which supports the biologic plausibility of the primary result.

The results of the iPrEx study also reveal real challenges. First, the association between self-reported drug adherence and pharmacologic detection of the study drug was very poor, which underscores the need for better reporting tools to predict drug adherence. Second, although renal insufficiency was seen in a relatively small fraction of subjects and was reversible on drug discontinuation, this finding raises both safety and monitoring concerns regarding possibly cumulative toxic effects associated with large-scale exposure of at-risk persons to daily FTC–TDF therapy for an extended period. The side-effect profile for FTC–TDF was probably diluted, given the reported medication-compliance issues, and thus would probably be more substantial with full compliance. Third, and most worrisome, viral resistance to FTC was documented in both of the subjects who were found to have had acute HIV infection at enrollment. Secondary FTC resistance after exposure to the drug clearly developed in one of these subjects, and the second subject had indeterminate resistance on baseline testing but showed FTC resistance 4 weeks after enrollment. This raises very serious concern about the deployment of oral FTC–TDF in populations of men who have sex with men and who are at greatest risk for HIV acquisition and thus have an increased risk of undiagnosed acute HIV infection. In addition, persons who have other chronic viral infections, such as hepatitis B virus (HBV) infection, may have intermittent antiviral exposure as well, which could lead to the emergence of resistance or HBV rebound with the cessation of prophylactic FTC–TDF therapy. We await the follow-up data from subjects with chronic HBV infection in the iPrEx study to provide some insight here.

The results of the iPrEx study represent a significant advance in HIV-prevention research in providing the proof of concept that a combination antiretroviral drug in widespread clinical use in the treatment of chronic HIV infection reduces the risk of HIV acquisition in men who have sex with men. What will be the public health effect of these results? The overall reduction in HIV incidence in the FTC–TDF group was less than 50%. Although increased medication adherence would raise this degree of protection (along with the risk of potential side effects), what is the likelihood that such a regimen could be accomplished in an implementation program that lacks the intense reinforcement of adherence counseling provided in the context of a clinical trial? How can medication-use fatigue be mitigated over potentially many years of daily therapy? What are the potential long-term safety issues for healthy persons, as well as those with coexisting illnesses, such as diabetes or hypertension? What will the iPrEx results mean for other populations with a lower risk of HIV acquisition? What would be the effect of open-label FTC–TDF use on the prophylactic use of condoms, on knowledge of HIV-infection status (both for subjects and their partners), and on the frequency of casual sex?

The risks of daily FTC–TDF use include the troubling development of secondary antiretroviral resistance in treated persons with undiagnosed acute HIV infection and a low but measurable degree of renal toxicity. Adherence to a daily regimen was low, nondurable, and difficult to assess without pharmacologic testing, which has substantial implications for research that uses this measure of behavior for medication compliance. Thus, the potential implementation of preexposure prophylaxis with FTC–TDF will probably be considered for men who have sex with men and who are at very high risk for HIV infection. In such men, the benefits of preexposure prophylaxis would be maximized and the costs of screening for acute HIV infection and monitoring of renal function and antiretroviral-drug adherence would be best justified.

Because of these considerations, the implementation of FTC–TDF therapy will be especially challenging in resource-limited health care settings. New information on the use of intermittent antiretroviral prophylaxis before risk exposure in men who have sex with men and in other high-risk groups will be coming from ongoing clinical trials. Taken together with the results of the iPrEx study, these data are likely to place another arrow in the quiver for HIV prevention.

source: NEJM

Proteinuria and Glomerular Filtration Rate: Risk Factors for Acute Kidney Injury

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Proteinuria and low estimated glomerular filtration rate (eGFR) should both be considered when assessing a patient’s risk for — and prognosis after — acute kidney injury, according to a large study presented at the American Society of Nephrology’s annual meeting and published online in the Lancet.

Among more than 900,000 adults in Canada tracked for some 35 months, risk for acute kidney injury requiring hospital admission or dialysis increased with increases in proteinuria alone and with decreases in eGFR alone; heavy proteinuria plus low eGFR conferred the highest risk. In turn, acute kidney injury was associated with increased mortality at all levels of proteinuria and eGFR, but particularly in patients with heavy proteinuria and normal eGFR.

Commentators conclude that “urine dipsticks … might just be what the doctor ordered for starting to reverse worldwide trends in acute kidney injury.”

 

Family intervention for schizophrenia

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People with schizophrenia are more likely to experience a relapse within family groups when there are high levels of expressed emotion (hostility, criticism or over involvement) within the family, compared to families who tend to be less expressive of their emotions. There are several psychosocial interventions available involving education, support and management to reduce expressed emotion within families. In this review we compare the effects of family psychosocial interventions in community settings for the care of people with schizophrenia or schizophrenia-like illnesses.

Studies were conducted in Europe, Asia and North America with packages of family intervention varying among studies, although there were no clear differences in study design. Results indicated that family intervention may reduce the risk of relapse and improve compliance with medication. However data were often inadequately reported and therefore unusable. As this package of care is widely employed, there should be further research to properly clarify several of the short-term and long-term outcomes.

Probiotics for treating acute infectious diarrhoea

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Episodes of acute infectious diarrhoea remain a major disease burden throughout the world, especially in developing countries. They are due to infection by many different organisms. Most episodes are self-limiting and usually investigations are not done to identify the infectious agent. The main risk to health is dehydration and management aims to improve and maintain hydration status. However, rehydration fluids do not reduce the stool volume or shorten the episode of diarrhoea. Probiotics are “friendly” bacteria that improve health and are not harmful in themselves. A number of randomized controlled trials have been done to see whether probiotics are beneficial in acute infectious diarrhoea. We have searched for as many of these trials as possible and collected together the data in a systematic way to try to discover whether or not probiotics are beneficial in acute diarrhoea. We identified 63 trials, which included a total of 8014 people – mainly infants and children. Probiotics were not associated with any adverse effects. Nearly all studies reported a shortened duration of diarrhoea and reduced stool frequency in people who received probiotics compared to the controls. Overall, probiotics reduced the duration of diarrhoea by around 25 hours, the risk of diarrhoea lasting four or more days by 59% and resulted in about one fewer diarrhoeal stool on day 2 after the intervention. However, there was very marked variability in the study findings and so these estimates are approximate. We concluded that these results were very encouraging but more research is needed to identify exactly which probiotics should be used for which groups of people, and also to assess the cost effectiveness of this treatment.