HIV incidence data for FSW in Nassarawa – Report from Biotech Initative, Nigeria

HIV incidence data for FSW in Nassarawa – Report from Biotech Initative, Nigeria

We estimated the HIV incidence among commercial female sex workers (FSWs) in north central Nigeria using bimodal methodology. Using a cross-sectional study design, a total of 900 active FSWs between the ages of 18 and 35 years were recruited from 52 brothels within Nasarawa State, Nigeria.

A rapid test algorithm was used to determine their HIV status. The BED IgG–Capture enzyme immunoassay (CEIA) was applied on the HIV-seropositive samples to detect recent HIV-1 infection for the estimation of incidence among those with HIV infection.

Of the 900 FSWs tested, 335 (37.2%) were found to be positive for HIV. Of these, 63 showed evidence of recent infection. Using two third-generation BED analysis approaches that account for false-recent rate, an annualized adjusted HIV incidence of 11.97% (95% CI:8.51–15.43%) and 12.36% (95% CI: 8.18–16.34%) was observed; difference P > 0.05. In addition, 875 (97.2%) of the FSWs readily agreed to participate in HIV clinical trials.

The report of this study shows that there is a feasibility for conducting HIV prevention trials in Nigeria among FSW with a high incidence of HIV. The infrastructural and human capacity also exists. Also, the high proportion of recent HIV infections among FSWs in Nigeria also provided an enabling environment for future studies of HIV prevention.

 

Original article

Estimates of human immunodeficiency virus incidence among female sex workers in north central Nigeria: implications for HIV clinical trials

Joseph C. Forbia, Peter E. Entonua, Lulu O. Mwangib, Simon M. Agwale

2011 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd.

Treating HIV-infected People with Antiretrovirals Protects HIV-negative Partners from Infection

Treating HIV-infected People with Antiretrovirals Protects HIV-negative Partners from Infection

The study was designed to evaluate whether immediate versus delayed use of ART by HIV-infected individuals would reduce transmission of HIV to their HIV-uninfected partners and potentially benefit the HIV-infected individual as well.  Findings from the study were reviewed by an independent Data and Safety Monitoring Board (DSMB).  The DSMB recommended that the results be released as soon as possible and that the findings be shared with study participants and investigators. The DSMB concluded that initiation of ART by HIV-infected individuals substantially protected their HIV-uninfected sexual partners from acquiring HIV infection, with a 96 percent reduction in risk of HIV transmission. HPTN 052 is the first randomized clinical trial to show that treating an HIV-infected individual with ART can reduce the risk of sexual transmission of HIV to an uninfected partner.

NHVMAS wants to thank the team for a wonderfully implemented study that has given us evidence about not just the possible role of HIV treatment in HIV prevention, but also the potential impact of early HIV treatment in reducing morbidity and mortality.

Read more details about the study below

Men and women infected with HIV reduced the risk of transmitting the virus to their sexual partners by taking oral antiretroviral medicines when their immune systems were relatively healthy, according to findings from a large-scale clinical study sponsored by the National Institute of Allergy and Infectious  Diseases (NIAID), part of the National Institutes of Health.

The clinical trial, known as HPTN 052, was slated to end in 2015 but the findings are being released early as the result of a scheduled interim review of the study data by an independent data and safety monitoring board (DSMB). The DSMB concluded that it was clear that use of antiretrovirals by HIV-infected individuals with relatively healthier immune systems substantially reduced transmission to their partners. The results are the first from a major randomized clinical trial to indicate that treating an HIV-infected individual can reduce the risk of sexual transmission of HIV to an uninfected partner.

“Previous data about the potential value of antiretrovirals in making HIV-infected individuals less infectious to their sexual partners came largely from observational and epidemiological studies,” said NIAID Director Anthony S. Fauci, M.D. “This new finding convincingly demonstrates that treating the infected individual—and doing so sooner rather than later—can have a major impact on reducing HIV transmission.”

 

Led by study chair Myron Cohen, M.D., director of the Institute for Global Health and Infectious Diseases at the University of North Carolina at Chapel Hill, HPTN 052 began in April 2005 and enrolled 1,763 couples, all at least 18 years of age. The vast majority of the couples (97 percent) were heterosexual, which precludes any definitive conclusions about effectiveness in men who have sex with men. The study was conducted at 13 sites in Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, the United States and Zimbabwe. The U.S. site collected only limited data because of difficulties enrolling participants into the study. However, data from one serodiscordant couple at the site was included in the DSMB’s analysis. At the time of enrollment, the HIV-infected partners (890 men, 873 women) had CD4+ T-cell levels—a key measure of immune system health—between 350 and 550 cells per cubic millimeter (mm³) within 60 days of entering the study. The HIV-uninfected partners had tested negative for the virus within 14 days of entering the study.

 

The investigators randomly assigned the couples to either one of two study groups. In the first group, the HIV-infected partner immediately began taking a combination of three antiretroviral drugs. In the second group (the deferred group), the HIV-infected partners began antiretroviral therapy when their CD4 counts fell below 250 cells/mm³ or an AIDS-related event, such as Pneumocystis pneumonia, occurred. Throughout the study, both groups received HIV-related care that included counseling on safe sex practices, free condoms, treatment for sexually transmitted infections, regular HIV testing, and frequent evaluation and treatment for any complications related to HIV infection. Each group received the same amount of care and counseling.

 

In its review, the DSMB found a total of 39 cases of HIV infection among the previously uninfected partners. Of those, 28 were linked through genetic analysis to the HIV-infected partner as the source of infection. Seven infections were not linked to the HIV-infected partner, and four infections are still undergoing analysis. Of the 28 linked infections, 27 infections occurred among the 877 couples in which the HIV-infected partner did not begin antiretroviral therapy immediately. Only one case of HIV infection occurred among those couples where the HIV-infected partner began immediate antiretroviral therapy.

 

This finding was statistically significant and means that earlier initiation of antiretrovirals led to a 96 percent reduction in HIV transmission to the HIV-uninfected partner. The infections were confirmed by genetic analysis of viruses from both partners.

Additionally, 17 cases of extrapulmonary tuberculosis occurred in the HIV-infected partners in the deferred treatment arm compared with three cases in the immediate treatment arm, a statistically significant difference. There were also 23 deaths during the study. Ten occurred in the immediate treatment group and 13 in the deferred treatment group, a difference that did not reach statistical significance.

The study was designed to evaluate whether antiretroviral use by the HIV-infected individual reduced HIV transmission to the uninfected partner and potentially benefited the HIV-infected individual as well. Additionally, the study was designed to evaluate the optimal time for a person infected with HIV to initiate antiretrovirals in order to reduce HIV-related sickness and death. Based on their analysis, the DSMB recommended that the deferred study arm be discontinued and that the study participants be informed of the trial’s outcome.

“We want to thank the study participants for making such an important contribution in the fight against HIV/AIDS. We think that these results will be important to help improve both HIV treatment and prevention,” said Dr. Cohen.

Study participants are being informed of the results. Individuals who became HIV-infected during the course of the study were referred to local services for appropriate medical care and treatment. HIV-infected participants in the deferred treatment group will be offered antiretroviral therapy.  The study investigators will continue following the study participants for at least one year.

The study was conducted by the HIV Prevention Trials Network, which is largely funded by NIAID with additional funding from the National Institute on Drug Abuse and the National Institute of Mental Health, both part of the NIH. Additional support was provided by the NIAID-funded AIDS Clinical Trials Group. The antiretroviral drugs used in the study were made available by Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/Viiv Healthcare and Merck & Co., Inc.

The 11 HIV drugs that were used in various combinations included the following:

• atazanavir (300 mg once daily)

• didanosine (400 mg once daily)

• efavirenz (600 mg once daily)

• emtricitabine/tenofovir disoproxil fumarate (200 mg emtricitabine/300 mg tenofovir disoproxil fumarate once daily)

• lamivudine (300 mg once daily)

• lopinavir/ritonavir 800/200 mg once daily (QD) or lopinavir/ritonavir 400/100 mg twice daily (BID)

• nevirapine (200 mg taken once daily for 14 days followed by 200 mg taken twice daily)

• ritonavir (100 mg once daily, used only to boost atazanavir)

• stavudine (weight-dependent dosage)

• tenofovir disoproxil fumarate (300 mg once daily)

• zidovudine/lamivudine (150 mg lamivudine/300 mg zidovudine taken orally twice daily)

For additional information about the HPTN 052 study, see the Questions and Answers. Visit the NIAID HIV/AIDS Web portal for more information about NIAID’s HIV/AIDS research.

Adaptive Clinical Trials Design – Part II

Adaptive Clinical Trials Design – Part II

Moderator’s Note: Please if you have questions or clarification to be made about Adaptive clinical Trial design, please do note we have the author of this piece online who will be ready to give further details and answer all questions. The part I of this posting was posted earlier. We hope to send in a three more postings to help us all understand this evolving concept for HIV prevention research. Happy reading.

In the clinical trials realm, Adaptive Clinical Trial Design (ACTD) is a clinical trial methodology that is rapidly gaining popularity and acceptance.  The primary reason for this phenomenon is due to the increasing cost of operating clinical trials which is often the by-product/causality of high failure rates of clinical trials.  ACTD has many advantages to facilitate the effectiveness of clinical trial operations.  However, as a relatively new methodology, it does have its challenges as well.

In this segment of our three-part article on Adaptive Clinical Trial Designs, we will (1) provide an overview on what ACTD is, (2) describe how it differs from the standard clinical trials designs, and (3) briefly highlight some of the advantages and disadvantages of ACTD.   In subsequent articles, we will (1) describe in greater details the pros/cons of ACTD, (2) describe regulatory authorities perspective and guidance on the topic and (3) offer recommendations on how to implement ACTD.

So, what exactly is Adaptive Clinical Trial Designs?  In accordance to the 2010 FDA Guidance for the industry on “Adaptive Design Clinical Trials for Drugs and Biologics,â€� an adaptive design clinical study is defined as:

A study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study.  Analyses of the accumulating study data are performed at prospectively planned time points within the study, can be performed in a fully blinded manner or in an un-blinded manner, and can occur with or without formal statistical hypothesis testing.

It has been argued by some that researchers do routinely modify clinical studies during the course of the studies via aProtocol Amendment� or Protocol Modification.� Modification in clinical trials may include administrative changes, early trial termination, addition/removal of treatment arms, changes in trial sample population size, and treatment arm allocation regimen.  How so, does this then differentiate ACTD from standard or conventional clinical trial designs?

There are two operative terms in the above definition for adaptive studies:  prospectively and modification.   Conventional clinical trial designs often use fixed or pre-determined sample sizes that do not use adaptive elements.  In other words, with ACTD, anticipated changes are planned before the study commences and adjusted accordingly.  On the other hand, with conventional studies, changes/amendments are allowed to be made after the commencement of a study for safety or administrative reasons if they do not impact the integrity of the data collected or statistically alter the initial statistical design or hypothesis of the study.

As described in the aforementioned FDA Guidance on Adaptive Design Clinical Trials, the three main advantages for adaptive clinical trials are that it:

•         Allow studies to be operated more efficiently and provides the same information

•         Increases the likelihood of success on the study objective

•         Yields improved understanding of the treatment’s effect (e.g., better estimates of the dose-response relationship or subgroup effects, which may also lead to more efficient subsequent studies).

The advantages, however, need to be cautiously weighed with the increase likelihood of introducing study bias with a poorly designed or poorly implemented adaptive methodology.  This is a major disadvantage and concern that is shared by regulatory authorities such as the FDA, drug developers, and the end users (i.e., customers).

As previously mentioned, this is simply a brief introduction to adaptive clinical trials methodology.  Additional details will be provided in subsequently articles.  However, for those eager to immediately learn more about Adaptive Clinical Trials Designs, below are three recommended readings:

1. Guidance for Industry . Adaptive Design Clinical Trials for Drugs & Biologics.  US Department of Health and Human Services; Food and Drug Administration.  February 2010.

2. The Agile Approach to Adaptive Research.  Written by Michael Rosenberg.  Published by John Wiley & Sons, February 2010.

3. Adaptive Clinical Trials: The Promise and the Caution.  Written by Donald Berry.  Published in Journal of Clinical Oncology, December 2010.

Adaptive Trial Design 1: An Overview

Adaptive Trial Design 1: An Overview

Adaptive trial design refers to a clinical trial methodology that allows trial design modifications to be made after patients have been enrolled in a study, without compromising the scientific method. In order to maintain the integrity of the trial, these modifications should be clearly defined in the protocol.

When designed well, an adaptive trial empowers sponsors to respond to data collected during the trial. This is achieved by re-focusing the trial in a way that maximises the impact of each subject’s contribution. Examples of adaptive trial designs include dropping a treatment arm, modifying the sample size, balancing treatment assignments using adaptive randomisation or simply stopping a study early for success or failure.

In a standard trial, safety and efficacy data are collected and reviewed by a monitoring board during scheduled interim analyses. However, aside from stopping a study for safety reasons, very little can be done in response to that data. Often, a whole new study must be designed to further investigate key trial findings.

In an adaptive trial, the sponsor might have the option of responding to interim safety and efficacy data in a number of different ways, including narrowing the trial focus or increasing the patient population. An example of narrowing the trial focus includes removal of one or more of the treatment arms based on predetermined futility rules. Alternatively, if the data available at the time of the review do not allow for a clear decision between utility and futility, it might be decided to expand the enrolment of patients on one or more treatment arms beyond the initially targeted sample size.

Another example of adaptive design is the response-adaptive. In a response-adaptive setting, patients are randomised to treatment arms based on the response to treatment of previous patients. In a response adaptive trial, real-time safety and efficacy data can be incorporated into the randomisation strategy in order to influence subsequent adaptive randomisation decisions on a patient-by-patient basis. An example of response-adaptive randomisation is “play-the-winner”, which assigns patients to treatment arms that have resulted in fewer adverse events or better efficacy.

As these examples demonstrate, the adaptive design concept can be utilised in a number of different ways to increase trial flexibility. In a well-designed adaptive trial, that flexibility can result in lower drug development costs, reduced time to market and improved patient safety. Cost reduction is achieved by stopping unsuccessful trials earlier, identifying successful trials sooner, dropping unnecessary treatment arms or determining effective dose regimens faster.

Time to market can be accelerated by identifying successful trials sooner and reducing, or removing entirely, the lead time between trial phases, especially Phases II and III. Patient safety is improved because adaptive trials tend to reduce exposure to unsuccessful treatment arms (which are dropped early), and increase access to effective treatment arms (via response adaptive randomisation).

Article written by: Eva Miller, Manager of Biostatistical Services, Stephane Deleger, West Coast Business Development Manager, and Jim Murphy, Vice President of Business Development and Marketing at Interactive Clinical Technologies, Inc (ICTI)

The authors can be contacted at info@icti-almac.com

Full paper can be accessed at: http://www.pharmaceutical-int.com/article/implementing-and-managing-adaptive-designs-for-clinical-trials.html

Perceptive survey highlights growing interest in adaptive trial designs

Perceptive survey highlights growing interest in adaptive trial designs

DATE: 26 April 2011

SOURCE: Outsourcing-Pharma.com

AUTHOR: Alexandria Pesic

http://www.outsourcing-pharma.com/Clinical-Development/Perceptive-survey-highlights-growing-interest-in-adaptive-tria… 

Perceptive Informatics, the eClinical Solutions provider and Parexel subsidiary, has released the results of a global survey which shows a growing interest in the implementation of adaptive trial designs. Entitled “Implementing Bayesian Response Adaptive Trials,” the survey was conducted during a recent webinar presented by Perceptive and UK-based science and technology consultants, Tessella. It canvassed the opinion of more than 300 industry professionals representing a broad range of clinical, statistical and regulatory functions. The results revealed that 80 per cent of respondents were considering implementing some type of adaptive design in the next twelve months. Of that 80 per cent, 76 per cent were considering designs that drop treatment arms at fixed interim analyses. However, only 24 per cent of respondents said they expected to implement designs that regularly adjust the randomisation ratio throughout the study – a technique known as response adaptive design.

Commenting on the findings, Damian McEntergart, senior director of statistics and product support at Perceptive, said: “Following the FDA draft guidance on adaptive trials, increasing implementation of these designs has helped to alleviate regulatory acceptance concerns within the industry.” An important requirement for adaptive trials is the ability to include more dose levels in Phase II dose-finding studies without significantly increasing the number of study participants or the length of timelines.”