PrEP and Decreased Glomerular Filtration Rate
Original Investigation Research
Invited Commentary
Preexposure Prophylaxis A Path Forward Mitchell H. Katz, MD
Thirty years after the discovery of the human immunodeficiency virus (HIV), about 50 000 Americans and over 2 million persons worldwide are infected each year, most of them through sexual relations. 1 This occurs despite detailed Related article page 246 knowledge of how HIV is transmitted and the availability of a highly effective, cheap, safe method of HIV prevention, the condom, which in addition to its effectiveness in HIV prevention, also decreases the likelihood of other sexually transmitted diseases as well as unwanted pregnancies. Although it is easy as physicians to rhapsodize about the advantages of the condom, it has one notable limitation: you have to use it for it to work. Educating people about condoms is necessary but insufficient to stop the spread of HIV. While condoms have prevented untold numbers of infections, more education about condoms is not in and of itself going to stop HIV transmission. There are a variety of reasons people at high risk for HIV do not use condoms, at least not every time, including power dynamics in relationships that prevent a member of a couple (often a woman) from asserting her right to be protected; intimacy issues; denial; the feeling that becoming infected is inevitable; and having impaired judgment due to intoxication . And condoms can break or slip, making their use less than a foolproof method of avoiding HIV infection. Given the persistently high rates of new infection, public health officials and researchers have struggled to identify new ways of preventing infection. All would agree that a vaccine is the best solution, but to date the virus has eluded vaccine candidates. A spermicide, which women could insert without a male partner being aware of it, is an attractive option, but so far none has been shown to be sufficiently effective for use. Given the lack of alternatives, studies demonstrating that preexposure prophylaxis (taking a combination pill of emtricitabine and tenofovir disoproxil fumarate daily) can prevent HIV transmission have caused a great deal of excitement and consternation. Preexposure prophylaxis has been shown in randomized placebo-controlled trials to be effective in preventing HIV infection among men who have sex with men, 2 heterosexuals,3 and injection drug users.4 The consternation comes from multiple sources: (1) Is it safe to take antiretroviral medications for long periods (a high level of confidence of safety is needed, since the person is healthy and is taking the medication to prevent an infection that might not occur anyway)? (2) Will preexposure prophylaxis result in persons having more high-risk sex (a concern especially since preexposure prophylaxis does not protect against other STDs)? And (3) can we identify a group of patients for whom this is a sensible intervention, given that it must be taken daily and should be used with condoms since it is not 100% effective. jamainternalmedicine.com
On the question of adverse effects, the article by Mugwanya et al5 in this issue of JAMA Internal Medicine is reassuring. It is known that tenofovir is associated with declining renal function when taken by HIV-infected patients, but is the same true of healthy persons taking the medication for preexposure prophylaxis? The authors found, in a population with high adherence to preexposure prophylaxis, that decreases in estimated glomerular filtration rates were small and not progressive. While this is good news, it is important to note that the length of follow-up was a median of 18 months; individuals may take these medications for years. And in this vein it is possible that other adverse effects of tenofovir could become apparent with very-long-term use. But even if we agree that preexposure prophylaxis with emtricitabine and tenofovir is safe, is it a good idea, and for whom? Some advocates of HIV prevention have worried about the possibility that preexposure prophylaxis will result in increased high-risk sexual activities, overwhelming whatever benefits are gained by the preexposure prophylaxis. However, a prior study of heterosexuals found only small increases in unsafe sex with outside partners among persons in a preexposure prophylaxis trial once they were told that they were receiving the active drug with no increase in incident sexually transmitted diseases.6 Studies on this topic are limited, but I believe that persons who are so concerned about contracting HIV that they are willing to take a pill every day to prevent it are unlikely to be the ones taking the greatest risks. Of course, people must be counseled to continue to use condoms because of failures with preexposure prophylaxis and to prevent other sexually transmitted disease. This brings us to the crux of the problem: how large is the group of persons with all the necessary characteristics to most benefit from preexposure prophylaxis? Such persons would be at high risk for HIV but have sufficient resources (insurance or otherwise) to afford daily pills. They must also be willing to undergo the daily regimen even after it is explained to them that the protection is imperfect and that they should continue to use condoms. Knowledge of preexposure prophylaxis is low among atrisk persons.7 Therefore, the low rate of use cannot be attributed to patients choosing not to take it. It is not known how many more persons would choose preexposure prophylaxis if they fully understood its risks and benefits, but likely the rate of use would be higher than the current rate. As with other decisions concerning medical interventions that have both benefits and risks, the best path is a direct discussion between patients and their clinicians or HIV-prevention educators. In the case of preexposure prophylaxis, the first questions should be general ones about what strategies patients use to protect themselves against (Reprinted) JAMA Internal Medicine February 2015 Volume 175, Number 2
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Purdue University User on 06/10/2015
255
Research Original Investigation
PrEP and Decreased Glomerular Filtration Rate
HIV. Understanding the circumstances under which our patients are at risk for HIV will enable us to help patients determine whether preexposure prophylaxis is a good option for them. Future development of long-acting formuARTICLE INFORMATION
REFERENCES
Author Affiliations: Department of Health Services, Los Angeles County, Los Angeles, California; Deputy Editor, JAMA Internal Medicine.
1. Centers for Disease Control and Prevention. HIV/AIDS: HIV Basics: Basic Statistics. http://www .cdc.gov/hiv/basics/statistics.html. Accessed November 4, 2014.
Corresponding Author: Mitchell H. Katz, MD, Department of Health Services, Los Angeles County, 313 N Figueroa St, Room 912, Los Angeles, CA 90012 ([email protected]). Published Online: December 22, 2014. doi:10.1001/jamainternmed.2014.6798. Conflict of Interest Disclosures: The author receives royalties for a chapter on HIV in Lange’s Current Medicine Treatment and Diagnosis. No other disclosures are reported. Disclaimer: The views expressed are those of the author, and not of the government of the County of Los Angeles.
256
lations may make preexposure prophylaxis a better option for those who cannot comply with a daily regimen, but it will not resolve the more complicated issues of prescribing preexposure prophylaxis.
2. Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587-2599. 3. Baeten JM, Donnell D, Ndase P, et al; Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399-410. 4. Choopanya K, Martin M, Suntharasamai P, et al; Bangkok Tenofovir Study Group. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381 (9883):2083-2090.
5. Mugwanya KK, Wyatt C, Celum C, et al. Changes in glomerular kidney function among HIV-1–uninfected men and women receiving emtricitabine–tenofovir disoproxil fumarate preexposure prophylaxis: a randomized clinical trial [published online December 22, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014.6786. 6. Mugwanya KK, Donnell D, Celum C, et al; Partners PrEP Study Team. Sexual behaviour of heterosexual men and women receiving antiretroviral pre-exposure prophylaxis for HIV prevention: a longitudinal analysis. Lancet Infect Dis. 2013;13(12):1021-1028. 7. Al-Tayyib AA, Thrun MW, Haukoos JS, Walls NE. Knowledge of pre-exposure prophylaxis (PrEP) for HIV prevention among men who have sex with men in Denver, Colorado. AIDS Behav. 2014;18(suppl 3): 340-347.
JAMA Internal Medicine February 2015 Volume 175, Number 2 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Purdue University User on 06/10/2015
jamainternalmedicine.com
Original Investigation Research
Invited Commentary
Preexposure Prophylaxis A Path Forward Mitchell H. Katz, MD
Thirty years after the discovery of the human immunodeficiency virus (HIV), about 50 000 Americans and over 2 million persons worldwide are infected each year, most of them through sexual relations. 1 This occurs despite detailed Related article page 246 knowledge of how HIV is transmitted and the availability of a highly effective, cheap, safe method of HIV prevention, the condom, which in addition to its effectiveness in HIV prevention, also decreases the likelihood of other sexually transmitted diseases as well as unwanted pregnancies. Although it is easy as physicians to rhapsodize about the advantages of the condom, it has one notable limitation: you have to use it for it to work. Educating people about condoms is necessary but insufficient to stop the spread of HIV. While condoms have prevented untold numbers of infections, more education about condoms is not in and of itself going to stop HIV transmission. There are a variety of reasons people at high risk for HIV do not use condoms, at least not every time, including power dynamics in relationships that prevent a member of a couple (often a woman) from asserting her right to be protected; intimacy issues; denial; the feeling that becoming infected is inevitable; and having impaired judgment due to intoxication . And condoms can break or slip, making their use less than a foolproof method of avoiding HIV infection. Given the persistently high rates of new infection, public health officials and researchers have struggled to identify new ways of preventing infection. All would agree that a vaccine is the best solution, but to date the virus has eluded vaccine candidates. A spermicide, which women could insert without a male partner being aware of it, is an attractive option, but so far none has been shown to be sufficiently effective for use. Given the lack of alternatives, studies demonstrating that preexposure prophylaxis (taking a combination pill of emtricitabine and tenofovir disoproxil fumarate daily) can prevent HIV transmission have caused a great deal of excitement and consternation. Preexposure prophylaxis has been shown in randomized placebo-controlled trials to be effective in preventing HIV infection among men who have sex with men, 2 heterosexuals,3 and injection drug users.4 The consternation comes from multiple sources: (1) Is it safe to take antiretroviral medications for long periods (a high level of confidence of safety is needed, since the person is healthy and is taking the medication to prevent an infection that might not occur anyway)? (2) Will preexposure prophylaxis result in persons having more high-risk sex (a concern especially since preexposure prophylaxis does not protect against other STDs)? And (3) can we identify a group of patients for whom this is a sensible intervention, given that it must be taken daily and should be used with condoms since it is not 100% effective. jamainternalmedicine.com
On the question of adverse effects, the article by Mugwanya et al5 in this issue of JAMA Internal Medicine is reassuring. It is known that tenofovir is associated with declining renal function when taken by HIV-infected patients, but is the same true of healthy persons taking the medication for preexposure prophylaxis? The authors found, in a population with high adherence to preexposure prophylaxis, that decreases in estimated glomerular filtration rates were small and not progressive. While this is good news, it is important to note that the length of follow-up was a median of 18 months; individuals may take these medications for years. And in this vein it is possible that other adverse effects of tenofovir could become apparent with very-long-term use. But even if we agree that preexposure prophylaxis with emtricitabine and tenofovir is safe, is it a good idea, and for whom? Some advocates of HIV prevention have worried about the possibility that preexposure prophylaxis will result in increased high-risk sexual activities, overwhelming whatever benefits are gained by the preexposure prophylaxis. However, a prior study of heterosexuals found only small increases in unsafe sex with outside partners among persons in a preexposure prophylaxis trial once they were told that they were receiving the active drug with no increase in incident sexually transmitted diseases.6 Studies on this topic are limited, but I believe that persons who are so concerned about contracting HIV that they are willing to take a pill every day to prevent it are unlikely to be the ones taking the greatest risks. Of course, people must be counseled to continue to use condoms because of failures with preexposure prophylaxis and to prevent other sexually transmitted disease. This brings us to the crux of the problem: how large is the group of persons with all the necessary characteristics to most benefit from preexposure prophylaxis? Such persons would be at high risk for HIV but have sufficient resources (insurance or otherwise) to afford daily pills. They must also be willing to undergo the daily regimen even after it is explained to them that the protection is imperfect and that they should continue to use condoms. Knowledge of preexposure prophylaxis is low among atrisk persons.7 Therefore, the low rate of use cannot be attributed to patients choosing not to take it. It is not known how many more persons would choose preexposure prophylaxis if they fully understood its risks and benefits, but likely the rate of use would be higher than the current rate. As with other decisions concerning medical interventions that have both benefits and risks, the best path is a direct discussion between patients and their clinicians or HIV-prevention educators. In the case of preexposure prophylaxis, the first questions should be general ones about what strategies patients use to protect themselves against (Reprinted) JAMA Internal Medicine February 2015 Volume 175, Number 2
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Purdue University User on 06/10/2015
255
Research Original Investigation
PrEP and Decreased Glomerular Filtration Rate
HIV. Understanding the circumstances under which our patients are at risk for HIV will enable us to help patients determine whether preexposure prophylaxis is a good option for them. Future development of long-acting formuARTICLE INFORMATION
REFERENCES
Author Affiliations: Department of Health Services, Los Angeles County, Los Angeles, California; Deputy Editor, JAMA Internal Medicine.
1. Centers for Disease Control and Prevention. HIV/AIDS: HIV Basics: Basic Statistics. http://www .cdc.gov/hiv/basics/statistics.html. Accessed November 4, 2014.
Corresponding Author: Mitchell H. Katz, MD, Department of Health Services, Los Angeles County, 313 N Figueroa St, Room 912, Los Angeles, CA 90012 ([email protected]). Published Online: December 22, 2014. doi:10.1001/jamainternmed.2014.6798. Conflict of Interest Disclosures: The author receives royalties for a chapter on HIV in Lange’s Current Medicine Treatment and Diagnosis. No other disclosures are reported. Disclaimer: The views expressed are those of the author, and not of the government of the County of Los Angeles.
256
lations may make preexposure prophylaxis a better option for those who cannot comply with a daily regimen, but it will not resolve the more complicated issues of prescribing preexposure prophylaxis.
2. Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587-2599. 3. Baeten JM, Donnell D, Ndase P, et al; Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399-410. 4. Choopanya K, Martin M, Suntharasamai P, et al; Bangkok Tenofovir Study Group. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381 (9883):2083-2090.
5. Mugwanya KK, Wyatt C, Celum C, et al. Changes in glomerular kidney function among HIV-1–uninfected men and women receiving emtricitabine–tenofovir disoproxil fumarate preexposure prophylaxis: a randomized clinical trial [published online December 22, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014.6786. 6. Mugwanya KK, Donnell D, Celum C, et al; Partners PrEP Study Team. Sexual behaviour of heterosexual men and women receiving antiretroviral pre-exposure prophylaxis for HIV prevention: a longitudinal analysis. Lancet Infect Dis. 2013;13(12):1021-1028. 7. Al-Tayyib AA, Thrun MW, Haukoos JS, Walls NE. Knowledge of pre-exposure prophylaxis (PrEP) for HIV prevention among men who have sex with men in Denver, Colorado. AIDS Behav. 2014;18(suppl 3): 340-347.
JAMA Internal Medicine February 2015 Volume 175, Number 2 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Purdue University User on 06/10/2015
jamainternalmedicine.com
