An FDA warning regarding increased suicide risk in children and teens taking antidepressant drugs has led to an overall decrease in antidepressant prescribing for young patients, reports a study in the November issue of Medical Care. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health, a leading provider of information and business intelligence for students, professionals, and institutions in medicine, nursing, allied health, and pharmacy.
However, the decrease appears limited to patients with less-severe depression, and has been accompanied by increased use of psychotherapy, report Satish C. Valluri, Ph.D., M.P.H., and colleagues of University of Maryland, Baltimore.
Antidepressant Prescribing Decreases for Non-Major Depression
In March, 2004, the U.S. Food and Drug Administration issued a warning about a possible increase in suicidal thoughts and behavior in children and adolescents starting treatment for antidepressant drugs. Later that year, a stronger "black box" warning was added.
To analyze the impact of the warnings, the researchers analyzed rates of antidepressant prescribing for young patients with newly diagnosed depression from before to after March, 2004. The study included more than 40,000 children and adolescents diagnosed with depression from 2003 to 2006, identified from a large insurance database.
Youth diagnosed with depression after the FDA warning were 15 percent less likely to be prescribed antidepressant drugs. However, on more detailed analysis, the reduction in antidepressant use was limited to patients with diagnoses other than major depressive disorder. For this group of children with less-severe depression, antidepressant prescribing decreased by 21 percent.
In contrast, rates of antidepressant treatment were unchanged for children and adolescents with major depression. The trends in antidepressant prescribing were about the same for children (under age 12) as adolescents (aged 12 to 17).
While More Depressed Youth Receive Psychotherapy
As antidepressant prescribing decreased, more young patients received psychotherapy after being diagnosed with depression. The increase in psychotherapy was greater for children (31 percent), but still significant for adolescents (19 percent). The difference was most pronounced for youth receiving psychotherapy as their only treatment for depression: from 37 percent before the FDA warning to 44 percent afterward.
Before and after the warning, about 80 percent of children and teens received some type of treatment antidepressant, psychotherapy, or both within six months after being diagnosed with depression.
Previous studies had reported decreased use of antidepressants in young patients since the 2004 FDA warnings. The new study provides a more detailed evaluation, including comparison of children versus adolescents and patients with major depressive disorder versus less-severe depression. The results suggest that the decrease in antidepressant prescribing has been limited to patients with less severe depression who account for the great majority of depressed youth. Meanwhile, there has been no significant change in antidepressant treatment for children and teens with major depression.
At the same time, the use of psychotherapy alone as initial treatment for depression has increase especially among children under 12. "Together these findings suggest more clinically nuanced pediatric antidepressant prescribing patterns than previously found," Valluri and coauthors conclude. They urge further studies to evaluate the impact of reduced antidepressant prescribing in young patients with less-severe depression
Source: Wolters Kluwer Health
Results of the world's first efficacy trial of an HIV-prevention approach called oral pre-exposure prophylaxis, or PrEP, were released online in the New England Journal of Medicine today. Data from this trial, called iPrEx, indicated an estimated 43.8% reduction of new HIVinfections among men who took an antiretroviral tablet daily to prevent HIV, compared to those who took a placebo pill.
"This discovery alters the HIV prevention landscape forever. While this level of efficacy is relatively strong, PrEP is not quite ready for prime time and work remains before this strategy is rolled out. However, we are thrilled to have a new prevention option beyond male and female condoms visible on the horizon," said Jim Pickett, Director of Advocacy at AIDSFoundation of Chicago and Chair of IRMA �" International Rectal Microbicide Advocates.
The iPrEx trial evaluated the safety and efficacy of the antiretroviral (ARV) drug TDF/FTC (brand name Truvada) taken once daily for HIV prevention among HIV-negative gay men, transgender women, and other men who have sex with men (MSM).
The participants, 2,499 in all, included individuals from Peru, Ecuador, Brazil, South Africa, Thailand and the United States. Half the men were randomized into the active arm that received Truvada, and the other half were randomized into the placebo arm and received a look-alike pill with no active ingredient. The participants and the researchers did not know who was in either arm. Enrollment for the trial began in June 2007 and was completed in December 2009. The primary analysis of the results released today includes participants who were followed until May 1, 2010, or for an average of 14 months.
Each participant was tested for HIV at monthly trial visits and given intensive pre-and-post test counseling. Additionally, they were regularly screened for sexually transmitted infections and received condoms, making up a very robust prevention package.
At the end of the trial, there were 36 infections in participants who received Truvada and 64 in recipients who took the placebo. Researchers calculated that the use of Truvada reduced new HIV infections by an estimated 43.8% overall when compared to placebo. While there appeared to be few side effects reported by the men who were taking the Truvada tablet, it is clear that much more information is needed regarding long term safety of this drug.
Other PrEP trials are ongoing. Results from studies among heterosexuals in Africa and injection drug users in Thailand are expected next year.
It is important to emphasize the factors that led to successful use of Truvada to prevent HIV in iPrEx. Taking the pill regularly was one of the most important. Efficacy appeared to be higher among those participants who took the study drugs consistently. Men who did not take the pill regularly did not see a protective benefit. Regular HIV testing and ongoing monitoring by a physician was also critical. For this strategy to work, each of these pieces, including a doctor's prescription, need to be in place.
The study team found that about half of the men in the active arm of the trial were in fact not taking their pills regularly, if at all," said Pickett. "It is not clear why this happened, but it certainly suggests that alternate means of using ARVs to prevent HIV infection may be more acceptable for these men. The primary means of transmission among gay men and other MSM is through unprotected anal intercourse. If we develop an ARV as a gel or lubricant applied rectally �" a rectal microbicide �" it could be more acceptable for some individuals who don't like taking pills."
Many gay men and other MSM already use lubricants for anal intercourse, so they wouldn't have to modify their behavior to achieve higher levels of protection with a rectal microbicide formulated as a lubricant. Adopting a new behavior�"such as taking a pill every day�"can be a considerable challenge for some.
Dr. Ian McGowan, one of the principal investigators of the Microbicide Trials Network and Scientific Vice Chair of IRMA agreed. "The data from the iPrEx study are encouraging but the less than ideal adherence rate to oral PrEP clearly show that we need additional prevention approaches such as rectal microbicides that could be used by men and women at risk of HIV infection through unprotected receptive anal intercourse," he said.
The world's third rectal microbicide trial is currently underway with sites in Pittsburgh, Pennsylvania; Boston, Massachusetts; and Birmingham, Alabama. Scientists are testing the rectal safety and acceptability of tenofovir gel, a microbicide developed for vaginal use that has shown promise for preventing HIV through vaginal intercourse. Depending on the outcome of this new study, tenofovir gel could be further evaluated to determine if it can reduce the risk of HIV among both men and women who engage in receptive anal intercourse.
This new Phase I rectal microbicide study, known as MTN-007, aims to determine if rectal use of tenofovir gel is safe, and in particular, does not cause cells in the rectum to become more vulnerable to HIV. Investigators will also ask trial participants questions regarding the gel's desirability. The trial is planning to recruit a total of 60 men and women.
While the rectal microbicide field has gained significant momentum, more focus and resources are needed. In 2010, U.S. $7.2 million is being spent globally on rectal microbicide research. IRMA has calculated that annual investments must increase by 40% from 2011 �" 2014, to U.S. $10 million/year and must increase further to U.S. $44 million (a six-fold increase) in the years 2015 �" 2020. These targets need to be met to ensure a minimum of candidate products are moving through the research pipeline into late stage testing for effectiveness.
Just as we use a combination of drugs to treat individuals living with HIV, we need a combination approach to prevention. That approach should include male and female condoms, sterile syringes, and access to treatment as well as new interventions like PrEP, topical microbicides, and vaccines. Adequate funding must continue for all of the methods we currently have, and it must continue for the new strategies that are still being developed as well.
In a global context where millions of individuals do not have access to life saving medications, it is imperative that funding provided for PrEP accessibility not compete with funding for treatment. Treatment funding has not kept pace with the need.
IRMA congratulates the trial sponsors, scientific collaborators and partners who conducted this landmark trial, with special thanks to the 2,499 participants in the study who volunteered so much of their time and energy. Their extraordinary contribution to HIV prevention science brings us another step closer to a day without AIDS, and for that we are supremely grateful.
Source:
Jim Pickett
International Rectal Microbicide Advocates
A new report by the Joint United Nations Programme on HIV/AIDS (UNAIDS), released yesterday, shows that theAIDS epidemic is beginning to change course as the number of people newly infected withHIV is declining and AIDS-related deaths are decreasing. Together, this is contributing to the stabilization of the total number of people living with HIV in the world.
Data from the 2010 UNAIDS Report on the global AIDS epidemic shows that an estimated 2.6 million [2.3 million-2.8 million] people became newly infected with HIV, nearly 20% fewer than the 3.1 million [2.9 million-3.4 million] people infected in 1999.
In 2009, 1.8 million [1.6 million-2.1 million] people died from AIDS-related illnesses, nearly one-fifth lower than the 2.1 million [1.9 million-2.3 million] people who died in 2004.
At the end of 2009, 33.3 million [31.4 million-35.3 million] people were estimated to be living with HIV, up slightly from 32.8 million1 [30.9 million-34.7 million] in 2008. This is in large part due to more people living longer as access to antiretroviral therapy increases.
"We are breaking the trajectory of the AIDS epidemic with bold actions and smart choices," said Mr Michel Sidibé, Executive Director of UNAIDS. "Investments in the AIDS response are paying off, but gains are fragile-the challenge now is how we can all work to accelerate progress."
1 The 2008 estimate for the number of people living with HIV was revised to 32.8 million [30.9 million-34.7 million] within the range of the previous estimate. The revision was based on new data from countries, including data from population-based surveys such as in Mozambique.
Prevention is working
The 2010 report contains basic HIV data from 182 countries and includes country-by-country scorecards. The report gives new evidence that investments in HIV prevention programming are producing significant results in many of the highest burden countries.
From 2001 to 2009, the rate of new HIV infections stabilized or decreased by more than 25% in at least 56 countries2 around the world, including 34 countries in sub-Saharan Africa. Of the five countries with the largest epidemics in the region, four countries-Ethiopia, South Africa, Zambia and Zimbabwe-have reduced rates of new HIV infections by more than 25%, while Nigeria's epidemic has stabilized.
Sub-Saharan Africa continues to be the region most affected by the epidemic with 69% of all new HIV infections. In seven countries, mostly in Eastern Europe and Central Asia, new HIV infection rates have increased by 25%.
Among young people in 15 of the most severely affected countries, the rate of new HIV infections has fallen by more than 25%, led by young people adopting safer sexual practices. In South Africa, the rate of new HIV infections among 18-year-olds declined sharply from
A total of 63 countries were studied. For some countries with complex epidemics including multiple population groups with different risk behaviours as well as major geographic differences, such as Brazil, China and the ussian Federation, this type of assessment is highly complex and could not be concluded in the 2010 HIV stimation analysis.
1.8% in 2005 to 0.8% in 2008 and among women 15-24 years-old it dropped from 5.5% to 2.2% between 2003 and 2008.
In 59 countries including 18 of the 25 countries with the highest HIV prevalence, less than 25% of men reported having sex with more than one partner in the last 12 months. Eighty-four countries reported the same behaviour trends for women.
Condom use and availability have increased significantly. Eleven countries-from Burkina Faso, to India, and Peru-report more than 75% condom use at last higher-risk sex. Data from 78 countries show that condom use among men who have sex with men was more than 50% in 54 countries. Reports of condom use by sex workers are also encouraging. In 69 countries, more than 60% of sex workers used a condom with their last client.
Access to HIV prevention services including harm reduction programmes for people who inject drugs has reached 32%-far short of what is needed to protect drug users from HIV worldwide. Even though many countries have included male circumcision in their prevention programmes, uptake at a population level remains low, and has not made a significant impact on the rate of new HIV infections.
New HIV infections slowing but still outpace treatment success by 2:1
Even though the number of new HIV infections is decreasing, there are two new HIV infections for every one person starting HIV treatment.
Investments in HIV prevention programmes as whole have not been adequate or efficiently allocated. HIV prevention investments comprise about 22% of all AIDS-related spending in low- and middle-income countries.
Declines in AIDS-related deaths
More people are living longer and AIDS-related deaths are declining as access to treatment has expanded. The total number of people on treatment increased by seven and half times over the last five years with 5.2 million people accessing life-saving drugs in 2009, compared to 700 000 in 2004. Over the course of the last year alone, an additional 1.2 million people received treatment-a 30% increase compared to 2008. In addition, there has been a secondary dividend of stopping new HIV infections with increased access to HIV treatment.
However, nearly twice the number of people-10 million-are waiting for treatment. New evidence shows that scaling up treatment has led to reductions in population mortality in high-prevalence settings. The results could be better-most people receiving antiretroviral therapy in sub-Saharan Africa start treatment late, which limits the overall impact of HIV treatment programmes. Countries have made slow but good progress in integrating tuberculosis and HIV programmes.
Significant progress in the virtual elimination of HIV to babies-handful of countries hold key to success
As more countries are using effective treatment regimens to prevent HIV transmission to babies, the total number of children born with HIV has decreased. An estimated 370 000 [230 000-510 000] children were newly infected with HIV in 2009, representing a drop of 24% from five years earlier.
Significant gains were observed in sub-Saharan Africa where new HIV infections among children have fallen 32%.
Just 14 countries now account for more than 80% of the gap in providing services to prevent mother-to-child transmission. Nigeria alone contributes to 32% of the worldwide gap.
Human rights are part of AIDS strategies but not fully implemented
The report also contains new data which shows that human rights efforts are increasingly being integrated into national AIDS strategies, with 89% of countries explicitly acknowledging or addressing human rights in their AIDS strategies and 91% having programmes in place to reduce stigma and discrimination. However, punitive laws continue to hamper access to AIDS-related services-79 countries worldwide criminalize same sex relations and six apply the death penalty. In the Asia-Pacific region, 90% of countries have laws which obstruct the rights of people living with HIV.
Resource demand outstripping supply
UNAIDS estimates that a total of US$ 15.9 billion was available for the AIDS response in 2009, US$ 10 billion short of what is needed in 2010 and funding from international sources appears to be reducing. Donor governments' disbursements for the AIDS response in 2009 stood at US$ 7.6 billion, lower than the US$ 7.7 billion available in 2008. Declines in international investments will affect low-income countries the most-nearly 90% rely on international funding for their AIDS programmes.
The report highlights the urgent need to sustain and scale up good investments and for countries to share the financial burden of the epidemic. Many countries are under-investing and need to increase their domestic financial commitments to sustain and scale up the AIDS response. A new Domestic Investment Priority Index developed by UNAIDS shows that almost half of the 30 countries in sub-Saharan Africa are spending less than their capacity- commensurate to their disease burden and availability of government resources. The index also shows that some developing countries with strong economies can meet a substantial portion of their resource needs from domestic sources alone.
Source:
UNAIDS
The results of the iPrEx PrEP effectiveness trial of once-daily TDF/FTC (brand name Truvada) in gay men, transgender women and other men who have sex with men are a landmark in HIVprevention research. The results, released on November 23, showed that TDF/FTC reduced risk of HIV infection by an average of 43.8%. This was calculated by looking at rates of infections among participants who received TDF/FTC plus a standard prevention package compared to those in the placebo arm who received a look-alike pill with no active drug, along with the prevention package. All of the men in the trial received the same package of proven prevention services. This is the first proof that an oral antiretroviral can be used to reduce risk of HIV among HIV-negative people. It is cause for great excitement and also raises important questions. This FAQ looks at some of the most important questions we have about PrEP and the iPrEx trial at this time.- What do the iPrEX data on TDF/FTC for HIV prevention tell us?
- What are the trial's statistical conclusions about the effectiveness of once-daily TDF/FTC for HIV prevention?
- How does an HIV prevention trial like iPrEx measure protection against HIV infection?
- What are the immediate implications of the iPrEx results for gay men and other men who have sex with men?
- What might happen next, and who decides?
- Aren't there concerns that people who take PrEP may develop drug resistance if they become HIV-infected? Did the iPrEx trial data provide any insight into how resistance to TDF/FTC may or may not develop in people who take PrEP?
- How would a partially effective intervention like PrEP using daily TDF/FTC be used in the real world? Isn't there a concern that PrEP or other partially effective interventions could do more harm than good - by causing people to stop using more effective interventions like condoms?
- Could the evidence that daily-dosing with TDF/FTC as PrEP reduces HIV risk encourage some men to take more risks than before?
- How important is adherence to the daily pill-taking regimen in the iPrEx trial, and what does that mean for real world use?
- Who would pay for PrEP using TDF/FTC? Isn't that drug expensive?
- How can PrEP using TDF/FTC be used in countries where gay men and other men who sex with men are not recognized legally?
- What does this result mean for the other ongoing PrEP trials?
- What are the participants in other PrEP trials and other HIV prevention trials being told about this result and how it affects the trials they are in?
- Will we need a confirmation trial of TDF/FTC as PrEP amongst men who have sex with men?
- Given the partial effectiveness seen in this trial and the CAPRISA 004 microbicide trial, shouldn't participants in other trials be offered 1% tenofovir gel or TDF/FTC?
- What is the status of follow up on the RV144 AIDS vaccine trial and the CAPRISA 004 microbicide trial?
- What is treatment as prevention? Is it related to PrEP?
- Which HIV prevention research results are expected next?
1) What do the iPrEX data on TDF/FTC for HIV prevention tell us?- Provision of once-daily TDF/FTC (tenofovir disoproxil fumarate combined with emtricitabine, brand name Truvada) reduced risk of HIV infection among gay men, transgender women and other men who have sex with men who were also receiving intensive counseling about safer sex, HIV testing, condoms, treatment for sexually transmitted infections and other prevention services on a monthly basis (see question 2).
- The trial underscores the importance of providing a comprehensive prevention package. All of the iPrEx participants received a full prevention package, including condoms, safer sex counseling and treatment of sexually transmitted infections. At each monthly clinic visit, participants were tested for HIV and counseled about daily use of the trial drug, a level of counseling and testing not easily achieved outside of a clinical trial.
- The trial also demonstrates that PrEP using daily TDF/FTC is only safe in people with confirmed HIV-negative diagnoses. The two cases of drug resistance documented in iPrEx occurred among two men who started taking TDF/FTC while in the earliest phases of HIV infection, and therefore did not test positive for HIV using the trial's diagnostics.
- iPrEx shows that adherence to the drug regimen is essential. Participants who received TDF/FTC and had detectable levels of drug in their blood were at much lower risk of HIV compared to participants who received TDF/FTC and had no drug in their blood. The trial also analyzed risk of infection as it related to reported rates of pill taking. Participants who reported taking their pills correctly and consistently the majority of the time had significantly lower risk of HIV infection compared to those who reported taking the pills less frequently.
- PrEP using TDF/FTC is a promising prevention intervention for gay men, transgender women and other men who have sex with men. The effectiveness was found among participants reporting unprotected anal intercourse at the time they enrolled in the trial. It may prove to have similar benefits in the context of vaginal sex and penile exposure, but these data will come from other ongoing trials (see question 12).
2) What are the trial's statistical conclusions about the effectiveness of once-daily TDF/FTC for HIV prevention?
Simply put, what the iPrEx statistics say is that it is highly likely that once-daily TDF/FTC provides some protection against HIV. The level of protection could be anywhere from 15.4 to 62.6 percent.
In all, 64 of the 1,248 study participants who received a placebo became HIV infected during the study, while 36 of the 1,251 participants receiving the study drug became HIV infected. This translates into an average 43.8 percent fewer infections overall among participants who received the study drug plus the prevention package, compared to those who received a placebo plus the prevention package. This analysis included all trial participants, whether or not they remained in the study for the duration of the trial or reported taking their pills regularly. An analysis that includes this full range of participants is known as an "intention to treat" analysis (or ITT). More specifically, the iPrEx trial data are based on a "modified intention to treat" analysis. The term "modified" here refers to the fact that men who were later found to be HIV-positive at the time that they first enrolled in the trial were excluded from the final analysis.
3) How does an HIV prevention trial like iPrEx measure protection against HIV infection?
Biomedical HIV prevention trials enroll HIV-negative volunteers and all of the participants receive a standard HIV prevention package. The exact components of this package vary by trial. Participants are randomly assigned to one of two groups: One group of participants receives the experimental intervention - such as TDF/FTC - and the other group receives a placebo that is indistinguishable from the experimental product.
Participants are followed over time. Those who test positive for HIV are immediately taken off of the study product (this could be the placebo or experimental product since trial site staff and participants do not know which arm each participant is in). At the end of the trial, the research team compares rates of HIV infections in the group of participants who received the experimental product plus the prevention package to HIV rates in those who received the placebo plus the prevention package. A finding of lower rates of infection among participants using the experimental product could indicate that the product has an HIV prevention benefit.
In the case of iPrEx, the standard prevention package included monthly HIV testing, risk reduction counseling, condom promotion, and sexually transmitted infection (STI) screening and treatment. Neither the participants nor the research team knew who had received the TDF/FTC tablets or the placebo tablets. All participants were counseled during their regular study visits that they should not assume that they had received the experimental product; that there was no guarantee that the product would provide any protection; and that they should continue using proven HIV prevention methods such as condoms.
4) What are the immediate implications of the iPrEx results for gay men and other men who have sex with men?
This study is of critical importance since it is the first to show that the drugs that treat HIV can be used to prevent infection in HIV-negative people. A PrEP strategy based on once-daily dosing with TDF/FTC has the potential to change HIV risk for gay men and other men who have sex with men. There's reason for enthusiasm that there is a new potential prevention tool for these communities that have been so hard hit by HIV. There's also reason for caution. Gay men and all other high-risk groups should discuss these results with their health providers to evaluate their implications. There is a need for immediate guidance from relevant public health authorities.
It is unrealistic to ignore the potential that some men may want to begin using PrEP immediately. Since the drug used in the study is licensed and available for use for HIV treatment, there is a need to act quickly to share clear, accurate information about the some of the trial's key conclusions among gay men and other men who have sex with men and their health providers. These include: PrEP using daily TDF/FTC was found to be safe and effective in the context of rigorous monitoring and HIV testing. Resistance emerged among two participants who started TDF/FTC without a confirmed HIV-negative diagnosis and were subsequently found to be HIV-positive. Side effects do occur and may affect the tolerability of TDF/FTC as a prevention strategy.
In addition, it is critical to stress that the trial evaluated once-daily dosing. There is no evidence for "disco dosing" or other strategies that use TDF/FTC or any other drug on other schedules. Obtaining drug from HIV-positive individuals will place those individuals at risk and should not be pursued.
We anticipate that in the coming weeks and months, national and international public health agencies, such as UNAIDS, the World Health Organization (WHO) and the US Centers for Disease Control and Prevention, will be issuing guidance to gay men and other men who have sex with men and to their health providers about off-label use of PrEP and the context in which it might be responsibly used.
5) What might happen next, and who decides?
At AVAC, we believe that there are roles for many stakeholders:- WHO/UNAIDS should move without delay to issue a statement clarifying the implications of the results for gay men and other men who have sex with men. They should also use this opportunity to stress that gays and lesbians are part of communities in each country around the world and therefore these results are relevant in all settings. In addition, this statement should address the broader timeline for results from other PrEP trials, providing a normative agency perspective on how countries with predominantly heterosexual epidemics might plan for and assess PrEP using TDF/FTC or other medications as a potential strategy.
- National authorities, especially those in the countries where iPrEx took place, need to urgently review the data and issue guidance on what is now known and not.
- Gilead (the manufacturer of TDF/FTC under the brand name Truvada) should provide updates on its conversations with the US Food and Drug Administration (FDA) and other regulatory bodies about the possibility of seeking a supplemental prevention indication for TDF/FTC.
- Civil society groups including (and especially) communities of gay and bisexual men and transgender women, AIDS treatment and prevention advocates and many others must work to understand what the iPrEx data do and do not show about daily use of TDF/FTC as PrEP. We must work together to help communities understand these findings and discuss, develop and disseminate advocacy agendas for the way forward.
6) Aren't there concerns that people who take PrEP may develop drug resistance if they become HIV-infected? Did the iPrEx trial data provide any insight into how resistance to TDF/FTC may or may not develop in people who take PrEP?
If someone becomes infected with HIV while using an ARV-based prevention strategy, then his or her virus will be exposed to whatever ARV drug or drugs are being used in that strategy. As a result, resistance to that drug could emerge. (Use of an antiretroviral in someone who is not infected with HIV cannot cause resistance.)
iPrEx trial participants were tested for HIV at every monthly study visit. Any participant who tested positive for HIV was asked to immediately stop taking their pills and to return all remaining medication (neither participants nor trial staff knew who had received TDF/FTC and who had received the placebo pill). By minimizing the time that any participant was taking TDF/FTC after becoming HIV infected, the risk of acquiring resistance was reduced.
All of the men who did become HIV-infected during the trial received HIV drug resistance testing. Among these men, no tenofovir resistance was detected. Three of the participants had HIV that was resistant to FTC. One of these participants was in the placebo arm and two in the TDF/FTC arm. After obtaining these results, the trial team went back to the earliest blood samples from these participants and determined that all three individuals were in the early stages of HIV infection at the time of enrollment. The infections were not detected because the men were not yet antibody positive to HIV.
Therefore, in this trial setting, resistance was only seen in men who were already infected with HIV when they started taking the study drug. This underscores the need to incorporate regular HIV testing into any program implementing ARV-based prevention in HIV-negative people. It is also essential to ensure that there are immediate public health messages directed to gay men, their health providers, and the general public, that the iPrEx data show the risk of drug resistance was only minimized when the strategy was used by men who were confirmed to be HIV-negative.
7) How would a partially effective intervention like PrEP using daily TDF/FTC be used in the real world? Isn't there a concern that PrEP or other partially effective interventions could do more harm than good - by causing people to stop using more effective interventions like condoms?
An intervention is only effective when it is used correctly and consistently. A condom, which reduces risk of HIV infection to nearly zero, is not effective at all if it remains in its wrapper. A strategy such as PrEP using daily TDF/FTC, which is less effective than a condom, may be easier for some people to use for a variety of reasons, including that the pill does not need to be taken during or just before intercourse. More consistent use of a partially effective product may therefore have a significant impact on both individual risk of HIV and incidence (the rate of new HIV infections in a community) and could provide some protection to those who are not able to consistently use condoms.
It is also important to remember that, in the iPrEx trial, daily TDF/FTC reduced risk of HIV infection among men who were also receiving sexually transmitted infection (STI) diagnosis and treatment, counseling, condoms and behavior change support in a medical setting that catered to and was accepting of gay men and other men who have sex with men. All of the elements of the package are important. What this shows is that a partially effective strategy can have a major impact when added to other existing interventions.
8) Could the evidence that daily-dosing with TDF/FTC as PrEP reduces HIV risk encourage some men to take more risks than before?
PrEP, or any other new prevention strategy, has the potential to change people's perception of their risk of HIV and, therefore, their risk-related behaviors. In the context of this trial, participants actually reported reduced risk behaviors: increased condom use and decreased number of sexual partners. This trend towards decreased risk taking has been observed in most biomedical prevention trials, but clinical trials do not necessarily predict what will happen in the real world.
It is possible that the introduction of PrEP might lead some gay men and other men who have sex with men to feel that they are now well-protected against HIV; some men might increase their numbers of partners or rates of unprotected sex. Other men might not change their behaviors or might start taking fewer risks as a result of the counseling and testing they receive before starting PrEP. It is impossible to know how behaviors would change without close monitoring and follow-up research. This information must be gathered - starting with the iPrEx follow-up trial (see question 14).
9) How important is adherence to the daily pill-taking regimen in the iPrEx trial, and what does that mean for real world use?
In the iPrEx trial, participants were instructed to take one of the pills provided by the trial every day. The trial team conducted a small substudy that looked at whether participants in the active drug arm (receiving TDF/FTC) had detectable levels of the drug in their blood. This substudy found that participants receiving TDF/FTC who had detectable drug levels were at significantly lower HIV risk compared to those who had no detectable levels. Put another way: Detectable drug level in the blood strongly correlated with protection.
There were additional data on adherence collected on the basis of what participants reported about their pill-taking behavior. In this analysis, participants who reported higher levels of adherence had a lower risk of HIV infection, compared to those who reported lower levels of adherence.
In real world settings, the effectiveness of this strategy will depend on correct and consistent use. Should PrEP be introduced, men who use it will need to be supported with effective and supportive adherence strategies. Alternative dosing regimens (i.e., intermittent PrEP, which could be before and after sex or on a less-than daily basis) also need to be evaluated for effectiveness and feasibility.
10) Who would pay for PrEP using TDF/FTC? Isn't that drug expensive?
The cost of TDF/FTC (brand name Truvada) varies by country. Truvada, the drug manufactured by Gilead, costs an estimated US$17 per day in the US. The generic formulation made by various companies including Matrix, Hetero, Cipla and Aurobindo and used in many developing countries costs from 39 cents to 45 cents per tablet. Cost will obviously be an issue and must be at the top of the agenda as we move toward potential use of PrEP in different communities around the world.
But the drug cost would be just one part of any future PrEP intervention using TDF/FTC; such a program would have to have comprehensive prevention services, counseling and testing. Moreover, it is vitally important that implementation of new prevention programs using ARVs in HIV-negative people not take resources away from treatment programs.
11) How can PrEP using TDF/FTC be used in countries where gay men and other men who sex with men are not recognized legally?
There are gay men and other men who have sex with men worldwide - every country should consider this a relevant issue. That said, it will be challenging to develop programs for gay men in countries where homosexuality is illegal or where men who have sex with men lack basic human rights - but there is a great need for new prevention interventions for these men. PrEP programs in these settings will need to be developed on a foundation of a human rights based approach to providing health care and broader civil liberties to gay men, lesbians, transgender people and other sexual minorities.
12) What does this result mean for the other ongoing PrEP trials? iPrEx is the only trial that has looked at daily TDF/FTC in the context of anal sex as the primary risk factor for HIV (i.e., among gay men and other men who have sex with men). Other ongoing trials are looking at PrEP in the context of penile-vaginal intercourse (i.e., women and heterosexual men) and/or injection drug use. (These trials also collect data on anal sex practices, but it is not the predominant mode of exposure as reported by participants.) Because of biological differences between anal and vaginal tissue, and between sexual and parenteral (via injection) exposure, these other PrEP trials must continue - with the following steps:- The Data and Safety Monitoring boards, or equivalent bodies, monitoring each of the ongoing trials should be informed of the iPrEx results.
- Trial teams in each of the countries where trials are ongoing should discuss the iPrEx results and their implications for current research and future planning with policy makers, civil society and other key stakeholders, as well as providing targeted updates to their participants (see below). Informed consent documents for all ongoing trials should be updated to include information about iPrEx and CAPRISA 004 (see question 13) so that prospective participants have a clear understanding of available data and the rationale for a placebo-controlled trial in their context.
13) What are the participants in other PrEP trials and other HIV prevention trials being told about this result and how it affects the trials they are in?
AVAC believes that trial participants should always be informed of relevant data in a manner reviewed and approved by the trial's Institutional Review Board. This may in some instances involve a revision to the informed consent process. In the case of iPrEx, the data are relevant to all ongoing studies of ARV-based prevention including both oral and topical strategies, and to planned and ongoing biomedical prevention trials in gay men and other MSM, including HVTN 505 (a Phase II vaccine trial among gay men in the US).
14) Will we need a confirmation trial of daily TDF/FTC as PrEP amongst men who have sex with men?
Additional data can be gathered in a range of studies, including demonstration projects, follow-up trials - such as the one the iPrEx team is planning - and others. Given the iPrEx data, additional placebo-controlled trials of this strategy in gay men and other men who have sex with men are not warranted. As mentioned, one important source of additional information will be a follow-up trial, which will begin in early 2011 and be open to all participants from the original iPrEx trial. All HIV-negative participants who choose to join this open-label trial will receive the active TDF/FTC pill along with an HIV prevention package and will be counseled on daily use of the drug. However, monitoring and HIV testing will be less frequent, with the goal of learning about PrEP safety and effectiveness in a "real world" context.
Other questions include: Would a PrEP strategy containing a single drug - tenofovir alone, or a different single ARV - be more or as effective as TDF/FTC? How can adherence be supported? What is effectiveness in the context of less frequent monitoring and HIV testing?
15) Given the data from iPrEx and CAPRISA 004, what are the ethical implications of continuing placebo-controlled trials of 1% tenofovir gel or TDF/FTC?
To answer this question, it can help to look at what existing relevant ethical guidance documents say on the matter. For example, the WHO/UNAIDS Ethical Guidance for Biomedical Prevention Trials (PDFonline here) states, "Researchers, research staff, and trial sponsors should ensure, as an integral component of the research protocol, that appropriate counselling and access to all state of the art HIV risk reduction methods are provided to participants throughout the duration of the biomedical HIV prevention trial. New HIV-risk-reduction methods should be added, based on consultation among all research stakeholders including the community, as they are scientifically validated or as they are approved by relevant authorities."
In this instance, the question is whether the new interventions, including oral TDF/FTC and 1% tenofovir gel have been "scientifically validated" on the basis of the data from a single trial. There are still many important questions that iPrEx leaves unanswered. These data can't be extrapolated to people at risk of HIV via heterosexual sex or injection drug use. Differences in biology of the vagina and rectum, and between HIV risk in sexual versus injection exposure make it essential that ongoing placebo-controlled trials looking at PrEP in these contexts must continue. More information is also needed for 1% tenofovir gel.
16) What is the status of follow up on the RV144 AIDS vaccine trial and the CAPRISA 004 microbicide trial?
The RV144 trial sponsors and other researchers are working to confirm and extend the observations of RV144 through laboratory research on samples collected from the more 16,000 trial volunteers. Additional small trials are already underway, and additional vaccine efficacy trials that build on the RV144 result are being designed and are likely to begin in 2013.
The CAPRISA team is now designing two studies to follow the 004 trial participants to answer key operational research questions that would help design future implementation programs should tenofovir gel get licensed. In October, the FDA indicated that it would consider both CAPRISA 004 and VOICE as pivotal trials despite the different dosing strategies. (The NIH-funded VOICE trial is currently evaluating the same 1% tenofovir vaginal gel used in CAPRISA 004 but inserted once daily, rather than before and after sex as in the 004 regimen. VOICE is also testing the effectiveness of two forms of oral pre-exposure prophylaxis (PrEP) to reduce the risk of HIV infection.) The FDA also indicated that it would want to see additional safety data, including in younger women and post-menopausal women.
In addition, there is ongoing discussion about two additional effectiveness trials of 1% tenofovir gel, which are currently being designed, but not yet approved or funded, including:- Follow-on African Consortium of Tenofovir Studies (FACTS consortium) 001 trial in South Africa would test the same dosing strategy as CAPRISA 004 in women from a variety of settings, include sexually active 16- and 17-year-olds, and it would gather more information on 1% tenofovir gel as a tool for HSV-2 prevention.
- The UK MRC's Microbicide Development Programme (MDP) 302 study would be conducted in other African countries and would compare two different dosing strategies - the CAPRISA 004 dosing regimen and use of a single coitally dependent dose.
17) What is treatment as prevention? Is it related to PrEP?
"Treatment as prevention" is a term describing the use of antiretroviral drugs that are used to reduce the risk of passing HIV to others. The strategy would function as a secondary benefit of antiretroviral treatment after its primary purpose of improving an individual's health. The rationale for this approach is that ARVs reduce viral load. Higher viral loads have been linked to increased risk of passing HIV to sexual partners. Treatment as prevention is an emerging area and there are different terms and phrases used to describe this approach, including "test and treat" and "testing and linkage to care plus," which recognizes that voluntary HIV testing and diagnosis is the first step to accessing care.
Treatment as prevention involves giving ARV drugs to HIV-positive people, while PrEP is for HIV-negative people. Find more information about treatment as prevention at www.avac.org/treatmentasprevention.
18) Which HIV prevention research results are expected next?
You can find more information about ongoing trials and expected results from AVAC's HIV prevention research timeline, available here.
Source:
Kay Marshall
AIDS Vaccine Advocacy Coalition (AVAC)
The New Jersey Assembly on Monday passed two bills that would restore funding to family planning clinics and expand eligibility for Medicaidcoverage of family planning services, the Asbury Park Press reports. The bills now go to the Senate for consideration in early December.The bills passed along party lines, but neither received the 54 votes needed to override a possible veto by Gov. Chris Christie (R). In June, Christie vetoed similar legislation that would have reversed state budget cuts to family planning clinics, and the Senate failed to override the measure on a party-line vote.
One of the bills (A 3274) would transfer $5 million in reserve funding to state family planning clinics. The measure passed 45-25 with nine abstentions. The bill would prohibit the money from being used to pay for abortion services. Republican critics of the measure argue that the funds would allow family planning clinics that provide abortions to use other sources of revenue for the procedure.
The other bill (A 3273), which passed 44-25 with 10 abstentions, would require New Jersey to apply to the federal government to expand Medicaid coverage for family planning services to people with incomes between 133% and 200% of the federal poverty level, as allowed under the federal health reform law (PL 111-148). Twenty-seven states already have secured federal permission for such expansions. If approved, New Jersey would receive more than $15 million in federal funds over two years by spending $1.1 million in state funds (Symons, Asbury Park Press, 11/22).
Reprinted with kind permission from http://www.nationalpartnership.org. You can view the entire Daily Women's Health Policy Report, search the archives, or sign up for email delivery here. The Daily Women's Health Policy Report is a free service of theNational Partnership for Women & Families.
© 2010 National Partnership for Women & Families. All rights reserved.
ش
Several newspapers published editorials and opinion pieces responding to Pope Benedict XVI's recent comments that condom use can be justified in some cases to prevent the spread of HIV. Summaries appear below.~ Boston Globe: Benedict's comments "should begin a discussion within the church focused more on humane ways to limit the spread of diseases like AIDS and less on an instrument -- the condom -- that the church has in the past vilified," a Globeeditorial states. It adds, "Benedict's acknowledgment that an across-the-board rejection of condoms could make the church a barrier to effective disease-fighting strategies is a welcome sign that the Vatican is not deaf to appeals from both inside and outside its walls" (Boston Globe, 11/23).
~ Los Angeles Times: It is "peculiar" that the pope used the example of a male sex worker when discussing condom use, when in fact, "in sub-Saharan Africa, AIDS is widely transmitted through heterosexual intercourse, including sex inside marriage," the Times writes in an editorial. Nonetheless, "Benedict has acknowledged the applicability to AIDS of the traditional Catholic doctrine of the 'double effect,'" which "holds that an action with an immoral effect can be permissible if it also has a good effect," according to the editorial (Los Angeles Times, 11/23).
~ Michael Gerson, Washington Post: The pope's condom remarks are "a welcome and necessary shift," columnist Gerson writes, adding that African Catholic leaders he knows "have long understood that a complete prohibition of condom use is unrealistic," especially for married couples and couples in which one partner is HIV-positive. Gerson continues, "The best AIDS prevention programs are idealistic about human potential and realistic about human nature. This seems to be where the pope is heading" (Gerson, Washington Post, 11/23).
~ Jonah Goldberg, Los Angeles Times: "It's a common trope among church critics to glibly suggest that the Vatican has the blood of millions on its hands because it doesn't back condom distribution, particularly in Africa," but this "is as absurd as it is unprovable," columnist Goldberg writes. He notes, "The church's opposition to corruption, ethnic violence and murder are just as pronounced and resolute, and yet such maladies persist in Africa as well." Goldberg continues that the "church's position is that the truest notes are those that not only celebrate life and love but cut through the ... racket of devouring time," suggesting that as "those notes become harder to hear, the answer isn't to stop playing them but to turn up the volume" (Goldberg, Los Angeles Times, 11/23).
Reprinted with kind permission from http://www.nationalpartnership.org. You can view the entire Daily Women's Health Policy Report, search the archives, or sign up for email delivery here. The Daily Women's Health Policy Report is a free service of theNational Partnership for Women & Families.
© 2010 National Partnership for Women & Families. All rights reserved.
The following summarizes select women's health-related blog entries.~ "Women's Rights Advocates Applaud New Executive Director of United Nations Population Fund,"Jodi Jacobson, RH Reality Check: Women's rights and reproductive health advocates "applauded" the recent appointment of Nigerian physician Babatunde Osotimehin as executive director of the U.N. Population Fund, Jacobson writes. Osotimehin is a professor of medicine at Nigeria'sUniversity of Ibadan and the African spokesperson for thePartnership for Maternal, Newborn and Child Health. Osotimehin previously worked as both minister of health and director general of Nigeria's National Agency for the Control of HIV and AIDS, where he "advocated strongly for evidence- and rights-based policies, even as his own government ... turned toward failed abstinence-only-until marriage programs to secure United States funding," Jacobson writes. Several women's health advocates noted Osotimehin's previous advocacy work on behalf of women, children and reproductive rights. Osotimehin "has made clear his own commitment to these issues," Jacobson writes. She quotes Osotimehin, who said, "We must invest far more in comprehensive reproductive health services, including those that address problems of HIV, in order to reach the girls and women who are not likely to use separate HIV services for fear of stigma and violence" (Jacobson, RH Reality Check, 11/19).
~ "Breastfeeding on Capitol Hill," Jessica Dweck, Slate's "XX Factor": A recent blog post by Rachel Campos-Duffy, wife of incoming-Rep. Sean Duffy (R-Wis.), discussed her experience breastfeeding in the Capitol's "nursing room," describing the incident as bipartisan moment. However, Dweck writes that "there is nothing bipartisan about it at all," adding, "After years of GOP leadership, a progressive Democratic woman [House Speaker Nancy Pelosi (D-Calif.)] took the initiative to use government funds to better accommodate new mothers and transform Congress into a more family-friendly work environment." Dweck continues, "Campos-Duffy's husband himself is part of [the] new batch of tea party-backed conservatives dispatched to D.C. to slash funding for extraneous government programs." She concludes, "While we don't yet know how Duffy will vote on these issues, with the Republicans' long history of hostility toward women and families, it's not hard to predict which kinds of programs and services will be deemed unnecessary when it's time to balance the budget" (Dweck, "XX Factor," Slate, 11/19).
~ "When Politics Trump Science, Women Lose," Emily Sullivan, RH Reality Check: In March 2009, a U.S. District Court directed FDA "to lower the over-the-counter age restriction" on the emergency contraceptive Plan B from 18 to 17, as well as to "re-review existing scientific evidence to decide whether an age restriction is even necessary," Sullivan writes. FDA has failed to carry out the order, and "[o]ne and a half years later, America's women are still waiting," she continues. "But we are not waiting silently," as the Center for Reproductive Rights last week "filed a motion of contempt of court against the FDA for failing to proceed in a timely manner," she writes. Sullivan argues, "As women's health advocates, we cannot accept the inaction of the FDA," adding, "Women, regardless of age, should not be denied an important and time sensitive contraception option." She concludes, "For the sake of women's health and for the sake of scientific integrity, the FDA must act now and reconsider its age restriction" (Sullivan, RH Reality Check, 11/22).
~ "Defending Your Rights? Study Finds Few Law Schools Offer Training in Reproductive Justice," Liz Kukura, RH Reality Check: A new study by Law Students for Reproductive Justice found that the "vast majority of law students ... lack any opportunity to study reproductive-rights legal issues formally," LSRJ's Kukura writes. The study found that 18% of law schools offered a reproductive-rights law course sometime in the past seven years, leaving a "significant gap in training for future legal advocates," she adds. The study shows that most law schools do not see reproductive rights as "a legitimate subject," she argues. However, schools have been slowly adding instruction on reproductive rights, with 41% of courses introduced in the past two years. One-third of courses on reproductive rights resulted from student advocacy, which demonstrates that students greatly influence changes in legal education, Kukura says. The study should serve as "a call to action" for law students to push for courses to "prepare them to be effective reproductive rights and justice advocates," Kukura writes (Kukura, RH Reality Check, 11/23).
~ "Woman Jailed for Getting Pregnant Dies from Medical Neglect," Alex DiBranco, Change.org's "Women's Rights": DiBranco writes that Amy Lynn Gillespie was jailed for becoming pregnant in violation of her probation in Allegheny County, Pa. "Yet this story comes to an even more tragic ending, because Gillespie died while in custody from advanced pneumonia," DiBranco adds. She argues that Gillespie should not have been jailed in the first place, because "to imprison a woman for becoming pregnant is a violation of her human rights, and should not be a condition of probation." DiBranco continues, "To then neglect her, when the very pregnant condition she was locked up for meant that she needed extra medical attention, is horrifying." Gillespie's mother has filed lawsuits against the jail warden, Allegheny Correctional Health Services, the country and a few other individuals. Meanwhile,New Voices Pittsburgh: Women of Color for Reproductive Justice is organizing a march to take place on Nov. 23 (DiBranco, "Women's Rights," Change.org, 11/22).
~ "Quick Hit: Birth Control in a Gel?" Serena Freewomyn, Feminists for Choice: The blog discusses Nestrogel, a "hormone cream that women can rub on their skin to get a dose of nesterone and estrogen, the hormones that control whether an egg is released each month." Although the cream "gives women one more option for the mode of delivery for their daily dose of hormones," Freewomyn notes that Nestrogel "has a few downsides that need to be addressed." To start with, the gel must be applied daily, she writes, adding, "If you're the type who doesn't want to take the pill every day, this might not be the best method of birth control for you." In addition, "creams have a risk of being absorbed by an unintended recipient," such as pets or partners, according to Freewomyn. "Consequently, patients using birth control cream need to make sure that the cream is applied in an inconspicuous area, so that dogs and/or partners aren't accidentally getting their own dose of birth control," she writes (Freewomyn, Feminists for Choice, 11/19).
Reprinted with kind permission from http://www.nationalpartnership.org. You can view the entire Daily Women's Health Policy Report, search the archives, or sign up for email delivery here. The Daily Women's Health Policy Report is a free service of theNational Partnership for Women & Families.
© 2010 National Partnership for Women & Families. All rights reserved.
