According to UNAIDS, about 2.6 million people became infected with HIV in 2009 – approximately 50,000 new infections each week. While HIV risk reduction counseling, provision of condoms, male circumcision and other methods have been shown to reduce HIV infections, thousands of people still become infected with HIV every day. The need for effective new prevention methods is critical, especially within populations with elevated risk for HIV infection, such as men and transgender women who have sex with men (MSM), and in geographic regions such as Africa, Asia and South America where HIV is spreading rapidly.

Pre-Exposure Prophylaxis (PrEP) is an HIV prevention strategy that uses HIV antiretrovirals (ARVs), drugs usually used to treat HIV infection, to reduce the risk of HIV acquisition among HIV-negative people. The theory behind PrEP is that taking HIV antiretroviral drugs may lead to concentrations of HIV-fighting drugs in the body that could help stop HIV infection if a person using PrEP is exposed to the virus.

The iPrEx study was the first human study of PrEP to report efficacy results. iPrEx found that a daily single-tablet dose of emtricitabine 200 mg/tenofovir 300 mg (FTC/TDF), commercially known as Truvada®, reduced HIV infection risk among men and transgender women who have sex with men (MSM) by an average of 44% overall. Truvada PrEP was found to be even more effective (up to 70% or more effective) among those who took the drug more consistently.

Trials are ongoing to test whether PrEP can reduce the risk of HIV infection via different routes of transmission, including sexual transmission between both heterosexual and same-sex partners and transmission through injecting drug use.

No. PrEP uses medicines that inhibit HIV. The medication used in PrEP does not contain HIV and cannot cause HIV infection.

Yes. The concept behind PrEP – using drugs to prevent disease -- is not new. Drugs are taken to prevent malaria, and can also be used to reduce the risk of developing tuberculosis and certain types of meningitis. Antiretroviral drugs are also used to reduce the chances of HIV transmission from mother to child.

Post-exposure prophylaxis, or PEP, is given to individuals after possible exposure to HIV. If administered within 3 days of exposure to HIV, PEP has been shown to reduce risk of HIV infection – but is not a substitute for other HIV prevention strategies.

Pre-exposure prophylaxis, or PrEP, is the approach used in the iPrEx study. With PrEP, uninfected individuals take an HIV treatment drug in order to build a concentration of the medication in their bodies. The theory is that the medicine may reduce the chances of HIV acquisition if an individual is exposed to the virus.

More than 20,000 people are currently participating in PrEP trials around the world. Enrolling, ongoing and recently completed PrEP trials are listed on the chart below, courtesy of AVAC: Global Advocacy for AIDS Prevention (http://www.avac.org/ht/d/sp/a/GetDocumentAction/i/3113)

Concerns about PrEP include:

• The potential costs and logistical challenges of ensuring widespread access to PrEP.

• The possibility that PrEP will lead some people to lower their guard against HIV and not use safer sex precautions consistently.

• The possibility that some people who become infected with HIV but who do not stop using PrEP could develop drug resistance. Because the drugs used in PrEP are not a full combination therapy regimen, continued use of PrEP after an individual is infected with HIV could cause mutations in the virus, making future treatment options potentially more complicated for the individual. There is also the possibility that if HIV mutates within an individual, leading to some degree of drug resistance, that person could transmit partially drug-resistant virus to others. One reason FTC/TDF is being studied for PrEP is that this drug combination is slow to produce drug resistance. The iPrEx study did not reveal significant levels of drug resistance among people using PrEP who became infected with HIV during the study. (For more information on PrEP and HIV drug resistance, please see question 51.)

Tens of millions of people are at active risk for HIV at any given time, and about 2.6 million people contract HIV every year. PrEP researchers are focusing on the populations at highest risk, which include men and transgender women who have sex with men (MSM), women and injecting drug users (IDU). iPrEx OLE is studying the long term safety of PrEP and its potential for reducing HIV infection risk among MSM.

iPrEx OLE is studying the impact of PrEP used once daily. Other studies using less frequent (intermittent) dosing strategies are underway or being planned. Those studies must be completed and evaluated before we know whether or how effective other PrEP dosing strategies may be.

Combination prevention is the best approach to reduce HIV risk. No single method of HIV prevention has been shown to eliminate all infections or risk of infection. Relying on just one HIV prevention method will provide only partial protection, at best. Using multiple methods of HIV protection is the best way to avoid infection.

PrEP is a scientifically promising approach to HIV prevention, and new strategies are needed to help reduce the 2.6 million new HIV infections that occur each year. The practical benefit of PrEP and how to best achieve it will have to be determined based on the prevention benefit PrEP provides to different populations, the steps required to manage any safety or resistance concerns and cost.

'Iniciativa Profilaxis Preexposicion" (Prexposure Prophylaxis Initiative), or the iPrEx study, was a Phase III clinical trial (a large-scale, randomized, double blind, multicenter study) designed to determine whether the daily oral single-tablet combination of two drugs used for HIV treatment -- tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg (FTC/TDF) -- can safely and effectively prevent HIV infection among men and transgender women who have sex with men (MSM), all of whom also received intensive safer sex counseling, condoms and the treatment or management of sexually transmitted infections (STIs).

In addition to studying the safety and effectiveness of daily FTC/TDF to help prevent HIV infection, the iPrEx study also examined whether side effects or HIV drug resistance were associated with the use of the PrEP study drug; whether people in the study changed their sexual risk behavior; and how well people in the study were able to take the daily tablet/pill (adherence).

iPrEx was the first large efficacy study of PrEP to be conducted in Africa, Asia, and North and South America. It was also the first large-scale HIV clinical trial conducted exclusively among men and transgender women who have sex with men (MSM) in Africa or Asia.

The iPrEx study now continues with the Open-Label Extension of the study, iPrEx OLE. For more information on iPrEx OLE, please visit http://www.iprexole.com

Participants at each of the 11 iPrEx clinical trial sites were randomly divided into two groups when they enrolled in the original trial.  Both groups received a comprehensive package of HIV prevention services including HIV prevention counseling and testing, condoms and medical care for any sexually transmitted infections.  One group received the study drug FTC/TDF once daily, while the other received a placebo, (a harmless substance that resembles the trial drug, but has no effect).

All participants were closely monitored throughout the randomized portion of the study (the portion of the study in which participants received drug or placebo), which concluded in August 2010, and for up to six months afterward.

After three years of preparatory work, the iPrEx study began in Lima on June 18th, 2007. The first participant was enrolled on July 10th, 2007, and the last was enrolled on December 18th, 2009. The discontinuation of the randomized phase of the study began on August 2nd, 2010 and the final study follow-up visit occurred in March of 2011.

The Open-Label Extension of the iPrEx study, iPrEx OLE, is expected to be fully enrolled by late 2011. Every participant will be followed for 72 weeks.

Yes. iPrEx is fully compliant with all national and international ethical standards and good participatory practices (GPP).

iPrEx was thoroughly and repeatedly reviewed by the Ethics Committees (ECs) and Institutional Review Boards (IRBs) at all of the study sites and the University of California San Francisco Committee on Human Research; the Ministries of Health of Peru, Ecuador and Thailand; the U.S. National Institutes of Health; the U.S. Food and Drug Administration; the Medical Research Council in South Africa and the Comissão Nacional de Ética em Pesquisa – CONEP in Brazil; and by an independent Data and Safety Monitoring Board (DSMB) comprising clinical research experts, statisticians and other representatives of the international academic research community, including representatives from the United States, Peru, South Africa, Brazil and Thailand.

The iPrEx study was conducted at the following 11 sites in Peru, Ecuador, Brazil, the United States, South Africa and Thailand:
• PERU: Asociación Civil Impacta Salud y Educación (Lima); Investigaciones Médicas en Salud (Lima); Asociación Civil Selva Amazónica (Iquitos)

• ECUADOR: Fundación Ecuatoriana Equidad (Guayaquil)

• BRAZIL: Instituto de Pesquisa Clinica Evandro Chagas -- FIOCRUZ (Rio de Janeiro); Projeto Praça Onze (Rio de Janeiro); Universidade de São Paulo (São Paulo)

• UNITED STATES: Fenway Health (Boston); San Francisco Department of Public Health (San Francisco)

• SOUTH AFRICA: Desmond Tutu HIV Foundation (Cape Town)

• THAILAND: Research Institute for Health Sciences (Chiang Mai)

These research institutions and countries were selected for this study because:

• Each site has extensive experience in clinical research and a solid record of compliance with all international clinical trial standards and regulatory aspects of the study, including providing safeguards for participants.

• Each site and each lead investigator have a demonstrated ability to conduct and involve their local communities in carrying out effective HIV prevention research.

• Governments in these countries have been engaged in HIV prevention and understand the importance and benefits of HIV research for their citizens.

• Men and transgender women who have sex with men (MSM) in these countries are highly affected by the epidemic, and it is essential that prevention research take place where the epidemic is.

The iPrEx study enrolled 2,499 sexually active HIV-negative men and transgender women who have sex with men (MSM) at high risk of contracting HIV at 11 study sites in Brazil, Ecuador, Peru, South Africa, Thailand and the United States.

iPrEx OLE is open to all HIV-uninfected participants from the original iPrEx study who wish to participate in the open-label extension phase of the study.

All iPrEx participants were born male (1.2% reported their current gender identity as female); are adults (median age of 24) and have an elevated risk for HIV infection.

MSM are among the groups most affected by HIV in a number of countries. Across different societies, where data are available, the prevalence of HIV infection is generally far higher among MSM than in the population at large. An article on HIV and MSM published in PLoS Medicine in December of 2007 reports that MSM have a markedly greater risk of being infected with HIV than the general population in low- and middle- income countries in the Americas, Asia and Africa. Studies indicate that HIV prevalence in MSM is 10 percent or higher in each of the countries in which iPrEx operates. Worldwide, MSM are in urgent need of improved HIV prevention, treatment and care.
Other studies are looking at PrEP for HIV prevention in other populations at increased risk for HIV in other countries – including among injection drug users in Thailand and among heterosexual women and men in Africa.

iPrEx is one of the largest and most geographically diverse HIV prevention studies to focus exclusively on HIV prevention in men and transgender women who have sex with men (MSM) to date. The iPrEx study, which is being conducted in the United States, South America, Asia and Africa, is the first large scale HIV prevention study to focus on MSM in Asia or Africa.

Men and transgender women who have sex with men (MSM) have selflessly led and consistently contributed to HIV prevention efforts since the beginning of the epidemic. Despite that record of leadership, however, and despite the grave impact of HIV on these communities worldwide, these populations have often been underrepresented in HIV prevention research.

Protecting volunteers is a central principle and focus of the iPrEx study. Participants are protected through:

Provision of full information and insistence on participant informed consent

Study volunteers are active and informed participants in and contributors to iPrEx. All participants were extensively counseled prior to enrolling in iPrEx about the purpose and design of the study, the fact that they might receive a placebo and the need to maintain strict safer sex precautions. All volunteers were required to pass a comprehension test to demonstrate that they understood the study and their rights as volunteers and to give their informed consent prior to participating. Participants were encouraged to ask questions and to discuss the trial with others, and were free to leave the trial at any time and for any reason without repercussions.

Safer sex and other HIV risk reduction services

All participants in the original iPrEx study and in the Open-Label Extension (iPrEx OLE) receive intensive risk reduction counseling and free condoms throughout the study. Participants also receive treatment or management of sexually transmitted infections and careful monitoring throughout the study.

Careful oversight by local and international monitoring boards

All iPrEx plans and materials have been extensively reviewed by the Ethics Committees (ECs)/Institutional Review Boards (IRBs) at all of the study sites and the University of California San Francisco Committee on Human Research. These ECs/IRBs meet all applicable international ethical standards. The study was also reviewed and approved by the Ministries of Health of Peru, Ecuador and Thailand, the U.S. National Institutes of Health, the U.S. Food and Drug Administration, the Medical Research Council in South Africa and the Comissão Nacional de Ética em Pesquisa – CONEP in Brazil.

iPrEx was also regularly monitored by a Data and Safety Monitoring Board (DSMB), an independent group of clinical research experts, statisticians and other representatives of the international academic research community, including representatives from the United States, Peru, South Africa, Brazil and Thailand.

All iPrEx participants were asked to return 4 and 8 weeks after their study medication was discontinued in August of 2010. Participants with hepatitis B infections were asked to continue coming to monitoring visits at weeks 12, 16, 20 and 24 after discontinuing study medication to monitor for possible hepatic flares. Participants in the bone mineral density and metabolic sub-study were asked to return 24 weeks after they stop taking the study medication for final tests.

The total cost of the iPrEx study was approximately U.S. $43 million. The randomized phase of the iPrEx study was funded by the U.S. National Institutes of Health (NIH) through a grant to the J. David Gladstone Institutes, a non-profit independent research organization affiliated with the University of California at San Francisco. Additional funding was provided by the Bill & Melinda Gates Foundation.

The company that manufactures FTC/TDF, Gilead Sciences, donated the medication used in the original iPrEx study and in iPrEx OLE, but is not involved in any other way in the development or implementation of the study or the analysis of its results.

Prior to the iPrEx results, no one knew whether PrEP would help protect people from HIV infection. Reliable information about the benefit of PrEP with FTC/TDF could only be obtained by comparing the active drug with a placebo among people who all received the same HIV prevention interventions such as risk reduction counseling, provision of condoms and management of STIs. Now that iPrEx has demonstrated a clear HIV prevention benefit from PrEP, the iPrEx OLE study will not use a placebo – everyone who wishes to participate in iPrEx OLE will receive the active PrEP drug.

iPrEx study personnel worked every day to help participants reduce their HIV infection risk by providing extensive counseling and support to help all study volunteers remain free of HIV. Very sharp reductions in risk behavior have been found among participants HIV prevention studies overall and in the iPrEx study in particular.

Despite intensive counseling and support, some people do not consistently protect themselves from HIV infection. Ultimately, it is by measuring the difference in new HIV infections between the drug and placebo arms of the study that we determine the benefit provided by PrEP with FTC/TDF, in addition to condoms, safer sex counseling and STI management on lowering the risk of HIV infection.

Careful medical monitoring and care was provided to participants throughout the original iPrEx study, and continue to be provided to participants in iPrEx OLE. In addition to primary medical care, treatment or management of STIs, vaccination against Hepatitis B (HBV) if appropriate and ongoing safer sex support and counseling, study participants receive all appropriate laboratory tests to monitor for possible HIV infection or any other abnormalities. Participants were also monitored and treated, if needed, for any side effect that may have been related to the study drug. Participants who became HIV infected during the study, despite safer sex counseling and the provision of condoms, also receive CD4 T cell count, viral load and drug-resistance testing, and are referred to antiretroviral treatment programs in the countries in which the study takes place. The same care is provided for participants in iPrEx OLE.

At sites where the practice is approved by regulatory and ethical bodies, study participants are reimbursed or receive vouchers for transportation expenses related to their participation in the study. Study participants also receive free treatment as needed for curable STIs. All iPrEx participants who could benefit from it were also offered free Hepatitis B vaccination

iPrEx found that PrEP with FTC/TDF provided an average of 44% (95% CI 15.4 to 62.6%*; P=0.005**) additional protection overall against HIV acquisition to men and transgender women who have sex with men (MSM) who also received a comprehensive package of prevention services including monthly HIV testing, counseling, condoms and STI management. This is a statistically significant level of efficacy and an important advance in HIV prevention research.

One hundred (100) HIV infections occurred among 2,499 participants during the study. Of these, 36 infections occurred in the study arm that received FTC/TDF, while 64 occurred in the arm that received placebo.

These results are based on a modified intention to treatment analysis (MITT), which includes data on all participants who were HIV-negative at the time of enrollment -- even if the participant was not taking the study pill for any reason.

PrEP was effective in a wide range of subgroups defined by age, educational level, ethnicity, alcohol use, male circumcision and HSV-2 infection – providing robust evidence that MSM who used PrEP realized protective benefits.

 

* Confidence interval (CI) is the range of effectiveness that the intervention could have, given the amount of evidence in hand. The modified intent-to-treat analysis of iPrEx indicates that it can be determined with 95% confidence that the efficacy of PrEP with FTC/TDF, which is estimated at 44%, could be as high as 62.6% or as low as 15.4% among all those who received active drug in the study, regardless of whether they used the pill or not.

** P-value measures how likely it is that these differences could have arisen by chance. The P-value of the modified intent-to-treat analysis in iPrEx is 0.005, indicating that there is only a 5 in 1,000 chance that the difference between infections in the study arm could have arisen by chance.

Yes. There are several indications that people who took the PrEP pill more consistently achieved higher levels of protection against HIV infection.

• iPrEx study participants who reported using the tablet on 50% or more of days, as measured by tablet counts, self-report, and dispensation records had 50.2% fewer HIV infections (95% CI 17.9-69.7%; P=0.006).

• Those who reported using PrEP on 90% or more of the days by the same measures had 72.8% fewer HIV infections (95% CI 40.7-87.5%).

These pill-taking measures rely on self-reports and are not objective, as self-reported pill use was significantly higher than pill use as measured by blood testing. However, they do indicate that this PrEP tablet, if used consistently, may offer a high level of protection study overall.

An additional analysis of PrEP drug levels in the blood of a sub-set of study participants indicates that more consistent use of PrEP produced a better protective effect: Every one of the HIV infections that occurred among study participants who received FTC/TDF PrEP occurred among people who had either no drug or very low levels of drug in their systems when the infection was discovered – indicating a very low degree of pill use.  In fact, only 9% of participants who became infected while receiving TDF/FTC had any detectable level of drug in their system.  By comparison, 51% (22 of 43) of the subset of participants tested who received FTC/TDF PrEP and remained seronegative had detectable levels of drug in their systems.  This indicates that people who became HIV-positive despite being in the active drug arm of the study were probably not using the PrEP drug regularly. 

The optimal timing and frequency of PrEP dosing is not known and requires further study.  The next generation of PrEP research should focus on ways to improve the use of PrEP as well as the reliability of pill use reporting.

The iPrEx study is a clear and important step forward for HIV prevention research. This finding means that PrEP has the potential to be a highly effective HIV prevention method for MSM when combined with standard HIV prevention tools such as counseling, provision of condoms and management of STI.

In addition to being the first study to report on and demonstrate the efficacy of PrEP in people, iPrEx is the first randomized clinical trial to demonstrate a protective effect for a biomedical intervention against HIV in MSM. These data address an important unmet need in public health, as HIV prevalence is higher in MSM than among other groups in almost all countries.

PrEP with FTC/TDF will not prevent all HIV infections. Oral PrEP does not prevent STIs such as gonorrhea, chlamydia, syphilis, herpes, warts or chancroid. PrEP does not prevent hepatitis C infection, which may be sexually transmitted in MSM. All MSM, whether they use PrEP or not, should have regular medical attention including periodic screening for STIs. Vaccination for HBV infection is important. Vaccination of MSM for human papilloma virus may be effective for prevention of warts and anal cancer. Condoms are effective for decreasing the transmission of many of these infections. MSM should communicate with partners about HIV test results and other aspects of sexual health.

For MSM who cannot consistently use condoms however -- especially those living in settings
with high rates of HIV -- even a partially protective intervention such as PrEP could be beneficial.

iPrEx found that PrEP with FTC/TDF is safe and well tolerated. Specifically, iPrEx found:

• No difference in moderate or severe adverse events (side effects or illnesses) between study participants who received the PrEP tablet and those who received placebo. On the placebo arm 164 participants developed a moderate or severe adverse event compared to 151 participants on FTC/TDF.

• No difference between the two study groups in a wide variety of laboratory tests including tests related to liver function, pancreatitis, electrolytes, glucose, phosphate, complete blood count and absolute neutrophil count.

Side effects related to use of the PrEP tablet in the study were infrequent and mild:

• Nine percent (9%) of individuals who received PrEP reported nausea in the first month on the study, compared to 5% of those who received placebo; after the first month there was no excess nausea among those who received the active pill.

• A small number of participants who received PrEP experienced increases in serum creatinine, a naturally occurring molecule filtered by the kidneys (2.1% vs. 1.2% in the placebo arm). All creatinine elevations resolved spontaneously or with discontinuation of the tablet. Investigators monitored renal (kidney) function throughout the study and found no serious problems.

• Unintentional weight loss of more than 5% was reported in 2.2% of people using PrEP compared with 1.1% of placebo users (P=0.04).

• Sixty-six (66) headache events were reported by 56 (4.5%) of participants in the FTC/TDF group, as compared to 55 headache events among 41 (3.3%) of the placebo group (p=0.10).

The iPrEx safety finding is consistent with safety studies of TDF as PrEP conducted by Family Health International among women in West Africa and by the U.S. CDC among MSM in the United States. It is also consistent with extensive experience with FTC/TDF as an approved therapy for HIV.

As with efficacy, low drug levels and pill taking among the study participants likely diminished the study's power to assess safety. More information will come from iPrEx OLE, iPrEx sub-studies and from other PrEP studies in the field.

Yes. Sub-studies of iPrEx and data from iPrEx OLE and other PrEP trials currently underway should provide important information to evaluate any possible subclinical effects of PrEP with FTC/TDF – effects that cannot be detected through regular laboratory testing -- including those that may affect bone mineral density, low-level drug resistance, proximal renal tubular function and HBV hepatic flares after stopping PrEP.

The use of highly sensitive PCR methods revealed very little drug resistance in the iPrEx study. No one in the study developed resistance to TDF, one of the drugs in the PrEP tablet/pill. Three cases of resistance to FTC were found: one in the placebo arm (meaning the person was infected with a drug resistant strain of HIV and did not develop drug resistance through the study) and two among the group that received PrEP. All three participants with FTC resistance were already HIV-infected at the time of enrollment in iPrEx, but their infection was too recent to be detected by HIV antibody tests.

The virus of the two study participants who enrolled in the study with acute but undetected HIV infection and who were randomized to the active drug arm, while exhibiting evidence of resistance to FTC, were also more highly susceptible to AZT and TDF and had normal susceptibility to other classes of drugs. In these two participants, the markers of FTC resistance decreased to undetectable levels (less than 0.5%) within 6 months of discontinuing PrEP

No evidence of resistance to FTC or TDF in iPrEx study participants who became HIV positive after being randomized into the active arm of the study.

While many effective treatments remain available for people with FTC resistance, it is important to make every effort to minimize the chances of drug resistance for anyone using PrEP. Approaches to minimizing resistance include ensuring regular HIV testing of people using PrEP and stopping PrEP immediately if an individual using PrEP becomes HIV-positive; and performing a simple health screen for viral symptoms to minimize the chances that a person with acute HIV infection, which may not be detected with regular antibody tests, begins use of PrEP.

Ten people with acute HIV infection – infection that was not detected with standard antibody tests at the time of study enrollment -- became part of the study. Their infections were detected after their enrollment by HIV RNA tests. If PrEP becomes available as an HIV prevention tool, efforts are needed to ensure that anyone experiencing any type of viral syndrome, which could look like a cold or flu, delay starting PrEP until their HIV-negative status can be reconfirmed. Individuals who have been exposed to HIV in the previous 72 hours should consult with his/her physician to start a 3-drug post-exposure prophylactic (PEP) regimen, as recommended by the US Centers for Disease Control.

Although self-reported pill use was high in both arms of the original iPrEx study, actual pill use and exposure to the PrEP drug may have been substantially lower. Blood drug testing indicates that approximately half of study participants had no detectable drug in their blood, despite higher self-reported levels of pill use. It is hoped that participants in the iPrEx OLE study will be able to achieve higher rates of PrEP pill use, as all participants know that they are receiving the active PrEP drug, and as it is now known that PrEP can reduce HIV infection risk.

Studies in a number of disease areas and across diverse populations show that tracking and accurately reporting on adherence is very difficult for individuals to do. Promoting the regular use of any medicine is a significant challenge with all health interventions. It may be particularly challenging to achieve regular pill-taking when the drug is designed to prevent rather than treat an illness.

Over-reporting of adherence can be due to multiple factors, including a participant simply forgetting whether or not they took their pill on a certain day and the desire to fulfill the goals of full participation in the study.

The next generation of PrEP research should focus on ways to improve the use of PrEP as well as the reliability of pill use reporting.

The data regarding HSV-2 acquisition in iPrEx is still being analyzed. Although FTC/TDF is not routinely used for treatment or prevention of HSV-2 infection, the CAPRISA 004 study recently showed that a TDF 1% vaginal gel provided some protection to women from the acquisition of herpes simplex type 2 infection (HSV-2). This protection may have been related to the high concentrations of drug that are achieved after topical vaginal dosing.

This analysis covers the time between June 18th, 2007, when iPrEx screened its first participant, and May 1st, 2010. Study drug discontinuation visits commenced August 1, 2010. An analysis of additional iPrEx study data gathered between May and March 2011 is being reported this year.

iPrEx does not answer questions about:

• The safety or efficacy of PrEP regimens using drugs other than FTC/TDF

• The safety or efficacy of PrEP in populations other than MSM

• The potential efficacy of alternative dosing regimens, (e.g., intermittent PrEP)

• How to best implement a PrEP program or the cost-benefit of doing so

• The potential public health impact of providing broad access to PrEP for HIV prevention

• The patterns of risk behavior that may occur now that more information is available about PrEP safety and efficacy

All HIV-negative iPrEx participants will be eligible to receive PrEP with FTC/TDF through iPrEx OLE, an 18-month open-label rollover study beginning in mid-2011. The rollover study will gather additional information on PrEP safety and efficacy, as well as on participant behavior and pill-taking.

Participants who are HIV-positive will also be able to receive continued monitoring of their health, including viral load and CD4 cell counts, trough iPrEx OLE.

Additional data from the iPrEx study will be collected, analyzed and released later in 2011. These will provide further information on a variety of safety and pill taking measures, including:

• Bone mineral density of participants in both study arms

• Drug resistance using more sensitive investigational assays

• Any evidence of low level kidney effects, based on urine analysis

• Patterns of exposure to the PrEP drug, based on drug levels in hair

• The occurrence of sexually transmitted infections, including herpes, in the study

Yes. The iPrEx study results cannot be extrapolated beyond MSM. Studies examining the potential impact of PrEP in other populations at high risk for HIV acquisition, including among women and injecting drug users, are underway and should definitely continue. Other studies looking at PrEP with different drugs or using different dosing strategies are also underway or planned and must continue. Developing effective HIV-prevention approaches involves multiple approaches and studies.

The need for new prevention methods is critical, especially within populations such as men who have sex with men (MSM) and in geographic regions such as Africa, Asia and South America, where HIV is spreading rapidly.

iPrEx provides critical information about the effectiveness of PrEP in reducing the risk of HIV infection among men and transgender women who have sex with men (MSM) who also received a comprehensive package of prevention services including HIV testing, risk reduction counseling, condoms and management of sexually transmitted infections. To date, very few approaches to the prevention of sexual HIV transmission have been rigorously proven. No other HIV prevention intervention has ever been rigorously proven in MSM, who carry a major burden of the global epidemic.

Whether iPrEx data alone are sufficient to warrant making PrEP available for HIV prevention, how and to whom is a decision to be made by regulatory authorities after careful review of the data and discussion with experts and people impacted by the epidemic. The iPrEx investigators urge WHO, UNAIDS and other global and national HIV policymaking bodies, especially those in the countries in which the iPrEx study took place, to meet promptly to review these findings and develop clear recommendations for next steps in the study and potential availability of PrEP.

Gilead Sciences operates an access program that facilitates access to TDF (branded as Viread) and FTC/TDF (branded as Truvada) at tiered prices in 130 developing countries based on a country's economic status and HIV prevalence.

Truvada (FTC/TDF) is made available for $26.25 per month and Viread (TDF) for $17.00 per month in countries with a gross national income (GNI) of less than $1,000 and/or an extremely high burden of HIV. Gilead access program prices for these drugs are $45.00 per month for Truvada (FTC/TDF) and $30.00 per month for Viread (TDF) in countries with a GNI of $1,000 to $3,000.

Gilead also partners with multiple generic manufacturers, providing a full technology transfer and allowing these partners to set their own prices. Generic FTC/TDF is made by Aurobindo, Cipla, Hetero and Matrix, and is available in some countries for as little as approximately U.S. $0.40 per day. (Source: Medecins Sans Frontieres: http://utw.msfaccess.org/drugs/tdf-ftc <http://utw.msfaccess.org/drugs/tdf-ftc> ). Gilead pursues registration for these drugs in all access program countries. Currently TDF is approved or filed in 119 countries and TDF/FTC is approved or filed in 118 countries. More information is available at http://www.gilead.com/pdf/GAP_Registration_Status.pdf)

Gilead has stated that it is working with the FDA and other appropriate regulatory agencies to determine whether the data from iPrEx and other oral PrEP trials would support a prevention indication

Gilead has stated that it will work with the appropriate government and public health agencies to ensure appropriate use and adequate supply of TDF and FTC/TDF should iPrEx and other oral PrEP trials provide sufficient evidence of safety and efficacy to make the drugs available for HIV prevention.

iPrEx OLE (OLE stands for Open Label Extension) is a continuation of the iPrEx study designed to provide additional information about the safety of PrEP and the behavior of people taking PrEP over a longer term. It is hoped that participants' knowledge that Truvada PrEP provides some protection against HIV infection, and the fact that all HIV-negative participants in iPrEx OLE know that they are receiving Truvada PrEP and not a placebo, will lead to increased use of the study drug by participants in iPrEx OLE, and increased protection against HIV infection.

iPrEx OLE will take place at 11 sites in Peru, Ecuador, Brazil, the United States, South Africa and Thailand. One additional site, the Ruth M Rothstein CORE Center in Chicago, Illinois (USA) will be added to the previous iPrEx study sites for the Open-Label Extension phase of the study.

iPrEx OLE is expected to be fully enrolled by late 2011 and every participant will be followed for 72 weeks. Participants will visit the study clinics at four, eight and 12 weeks, and every 12 weeks thereafter.

iPrEx OLE will gather additional information about the use of Truvada PrEP, including information on the long-term safety and efficacy of PrEP with FTC/TDF, pill taking and adherence, any changes in participants' sexual behavior, drug resistance, and any possible side effects including effects on bone mineral density and fat distribution.

The study is sponsored by the Division of AIDS (DAIDS) of the National Institutes of Health (NIH) through a grant to the Gladstone Institutes in San Francisco California. Gilead Sciences donates drug for iPrEx OLE, but does not contribute financially to the study and does not participate in its design, conduct or data analysis.