Comment
Middle Temple Library/Science Photo Library
When is good good enough for HIV-1 prophylaxis?
Published Online October 7, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70959-4 See Articles page 1055
1024
“The best is the enemy of the good”, wrote Voltaire, in 1772. This quote, in its many variations, has been used to point out that good solutions to problems can be passed over or actively discarded in the quest for an often elusive best or perfect solution. In The Lancet Infectious Diseases, Jared Baeten and colleagues1 report the final results of the Partners PrEP study, and suggest that one drug might be as good as two for HIV preexposure prophylaxis (PrEP). Partners PrEP was an extremely well done, randomised, double-blinded phase 3 trial of daily tenofovir disoproxil fumarate, alone or coformulated with emtricitabine, in the prevention of sexually acquired HIV infection in HIV serodiscordant couples in Kenya and Uganda.2 After the results of an interim analysis showed high levels of efficacy for both the single and combination drug groups (67% and 75%, respectively), the investigators rerandomised eligible patients from the placebo group to receive tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate, allowing for more precise efficacy estimation in the two active groups. Baeten and colleagues report that for the 4410 couples on active PrEP with one or more follow-up visits, final incidence of HIV-1 acquisition was 0·48 per 100 personyears in the combination drug group versus 0·71 per 100 person-years in the single drug group, a non-significant difference (hazard ratio 0·67, p=0·16). Do these results open up the option of tenofovir disoproxil fumarate alone for PrEP? In what situations might a single drug be an acceptable or optimal regimen? Both regimens have been shown to be highly efficacious. However, a head-to-head comparison has only been done in the Partners PrEP study, whereas in all other trials only one oral regimen was tested3–5 or the adherence was too low to accurately estimate efficacy.6 Tenofovir disoproxil fumarate alone had twothirds of the efficacy of the combination regimen, a potentially clinically relevant, albeit not significant, difference. Efficacy estimates were substantially closer in the comparison of drug detection in blood between infected and uninfected participants: 85% for tenofovir disoproxil fumarate and 93% for emtricitabine plus tenofovir disoproxil fumarate. Other reasons for prioritisation of one regimen over the other would be for superior tolerability, safety, drug
sensitivity, access, or cost-effectiveness. Both regimens had excellent safety and tolerability profiles. Renal dysfunction was rare and seemed reversible;2–6 small decreases in bone mineral density had no detectable clinical relevance,4 and both effects are associated with the tenofovir disoproxil fumarate in the regimens. Acquisition of resistant virus seems unlikely with either regimen because the prevalence of tenofovir disoproxil fumarate resistance globally is quite low,7 though the more common emtricitabine resistance seemed to have no effect on the combination regimen PrEP efficacy in non-human primate challenge models.8 The development of antiretroviral resistance while on PrEP if infection does occur, seems to be higher for users of emtricitabine plus tenofovir disoproxil fumarate than for users of tenofovir disoproxil fumarate alone (20% vs 5% in the Partners PrEP study on ultra-deep sequencing).9 This risk can be mitigated through careful screening before PrEP initiation and reinitiation. However, results of modelling studies suggest that PrEP would account for less than 4% of antiretroviral resistance at a population level over 20 years, most of the resistance coming from inadequate treatment of HIV-infected patients.10 Cost-effectiveness models suggest that PrEP would be cost effective in the USA11 and in developing countries,12 if targeted to individuals at highest risk. Although costs remain high for both regimens in the USA and other high-income countries, prices are quite low where generics are available, and substantially lower than the cost of treatment, in any case. In view of Baeten and colleagues’ data, tenofovir disoproxil fumarate alone might be a reasonable option for PrEP if cost or access would otherwise eliminate PrEP as an option. Why, then, has PrEP uptake been so slow globally? The results of four trials have shown substantial PrEP efficacy, likely exceeding 90% when adherence is high. With 50000 new infections every year in the USA and 2·3 million globally, surely there are many people who would benefit from PrEP. Arguments against offering PrEP often focus on the best form of prevention, variously defined as condoms, treatment for HIVinfected individuals, or clean injection equipment. All three of these options are vital, but none has been or www.thelancet.com/infection Vol 14 November 2014
Comment
likely will be sufficient alone to stop new HIV infections. PrEP might not be a perfect solution, but it is certainly an exceedingly good one. We must find ways to deliver PrEP to at-risk populations globally. Otherwise, as Voltaire is also quoted as saying, “Every man is guilty of all the good he did not do.” Susan Buchbinder San Francisco Department of Public Health, San Francisco, CA, USA [email protected] I have conducted PrEP studies funded by the National Institutes of Health. Gilead has provided drug for some of the PrEP trials in which I have been involved. 1
2
3
Baeten JM, Donnell D, Mugo NR, et al, for the Partners PrEP Study Team. Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial. Lancet Infect Dis 2014; published online Oct 7. http://dx.doi.org/10.1016/S1473-3099(14)70937-5. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012; 367: 399–410. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363: 2587–99.
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5 6
7
8
9
10
11
12
Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012; 367: 423–34. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med 2012; 367: 411–22. Marrazzo J, Ramjee G, Nair G, et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE Study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections; Atlanta, GA, USA; March 3–6, 2013. 26LB (abtrs). Chan PA, Huang A, Kantor R. Low prevalence of transmitted K65R and other tenofovir resistance mutations across different HIV-1 subtypes: implications for pre-exposure prophylaxis. J Int AIDS Soc 2012; 15: 17701. Cong ME, Mitchell J, Sweeney E, et al. Prophylactic efficacy of oral emtricitabine and tenofovir disoproxil fumarate combination therapy against a tenofovir-resistant simian/human immunodeficiency virus containing the K65R mutation in macaques. J Infect Dis 2013; 208: 463–67. Lehman DA, Baeten J, McCoy C, et al. PrEP exposure and the risk of lowfrequency drug resistance. 21st Conference on Retroviruses and Opportunistic Infections; Boston, MA, USA; March 3–6, 2014. van de Vijver DA, Nichols BE, Abbas UL, et al. Preexposure prophylaxis will have a limited impact on HIV-1 drug resistance in sub-Saharan Africa: a comparison of mathematical models. AIDS 2013; 27: 2943–51. Kessler J, Myers JE, Nucifora KA, et al. Evaluating the impact of prioritization of antiretroviral pre-exposure prophylaxis in New York City. AIDS 2014: published online Sept 10. Nichols BE, Boucher CA, van Dijk JH, et al. Cost-effectiveness of preexposure prophylaxis (PrEP) in preventing HIV-1 infections in rural Zambia: a modeling study. PLoS One 2013; 8: e59549.
Because of shared routes of transmission, 5–25% of the 34 million people with HIV worldwide are coinfected with either hepatitis B virus (HBV), hepatitis C virus (HCV), or both,1 with the highest number of co-infections in low-income countries. The negative effect of HIV infection on the progression of HBV and HCV infection is well established, with high rates of viral persistence, higher hepatitis viral load, and a more rapid progression to liver fibrosis and hepatocellular carcinoma in HIV-positive patients.2 In high-income countries, hepatic disease is the third highest cause of death in people with HIV after AIDS-related mortality and non-AIDS cancer deaths3, and hepatocellular carcinoma causes a quarter of liver-related deaths.2 Because of the increasing availability of antiretroviral therapy and the high burden of viral hepatitis, chronic hepatitis and its consequences are expected to become a leading burden of disease in resource-limited countries, although the true prevalence and clinical evolution of liver disease in low-income and middleincome countries are still largely unknown. In highly endemic regions such as Africa and Asia, the prevalence of HBV is estimated to be as much as 8% (10–15% in www.thelancet.com/infection Vol 14 November 2014
some countries), and HBV infection mostly occurs early in life through vertical or child-to-child transmission; the effect of hepatocellular carcinoma is likely to be even greater than estimated, particularly in Asia where HBV genotype C is highly prevalent.4 The clinical effect of viral hepatitis infection on the natural history of HIV infection is unclear. Some evidence suggests that viral hepatitis increases the risk of mother-to-child-transmission of HIV, accelerates HIVdisease progression, increases HIV viral setpoint, and blunts the response to antiretroviral therapy, resulting in a smaller and slower CD4 cell increase than reported in people without HBV or HCV. In The Lancet Infectious Diseases, Zhang and colleagues5 provide a unique overview of survival, virological response, and immunological response to antiretroviral therapy in a huge cohort of Chinese HIVpositive patients also infected with HBV, HCV, or both. To our knowledge, this cohort is the largest addressing this subject, and the most extensive study of triple infection reported so far. Although the prevalence of HBV co-infection in China reported by Zhang and colleagues (8·7%) is lower than that provided in
Imaginechina/Corbis
Hepatitis virus and HIV interactions
Published Online October 8, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70853-9 See Articles page 1065
1025
Middle Temple Library/Science Photo Library
When is good good enough for HIV-1 prophylaxis?
Published Online October 7, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70959-4 See Articles page 1055
1024
“The best is the enemy of the good”, wrote Voltaire, in 1772. This quote, in its many variations, has been used to point out that good solutions to problems can be passed over or actively discarded in the quest for an often elusive best or perfect solution. In The Lancet Infectious Diseases, Jared Baeten and colleagues1 report the final results of the Partners PrEP study, and suggest that one drug might be as good as two for HIV preexposure prophylaxis (PrEP). Partners PrEP was an extremely well done, randomised, double-blinded phase 3 trial of daily tenofovir disoproxil fumarate, alone or coformulated with emtricitabine, in the prevention of sexually acquired HIV infection in HIV serodiscordant couples in Kenya and Uganda.2 After the results of an interim analysis showed high levels of efficacy for both the single and combination drug groups (67% and 75%, respectively), the investigators rerandomised eligible patients from the placebo group to receive tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate, allowing for more precise efficacy estimation in the two active groups. Baeten and colleagues report that for the 4410 couples on active PrEP with one or more follow-up visits, final incidence of HIV-1 acquisition was 0·48 per 100 personyears in the combination drug group versus 0·71 per 100 person-years in the single drug group, a non-significant difference (hazard ratio 0·67, p=0·16). Do these results open up the option of tenofovir disoproxil fumarate alone for PrEP? In what situations might a single drug be an acceptable or optimal regimen? Both regimens have been shown to be highly efficacious. However, a head-to-head comparison has only been done in the Partners PrEP study, whereas in all other trials only one oral regimen was tested3–5 or the adherence was too low to accurately estimate efficacy.6 Tenofovir disoproxil fumarate alone had twothirds of the efficacy of the combination regimen, a potentially clinically relevant, albeit not significant, difference. Efficacy estimates were substantially closer in the comparison of drug detection in blood between infected and uninfected participants: 85% for tenofovir disoproxil fumarate and 93% for emtricitabine plus tenofovir disoproxil fumarate. Other reasons for prioritisation of one regimen over the other would be for superior tolerability, safety, drug
sensitivity, access, or cost-effectiveness. Both regimens had excellent safety and tolerability profiles. Renal dysfunction was rare and seemed reversible;2–6 small decreases in bone mineral density had no detectable clinical relevance,4 and both effects are associated with the tenofovir disoproxil fumarate in the regimens. Acquisition of resistant virus seems unlikely with either regimen because the prevalence of tenofovir disoproxil fumarate resistance globally is quite low,7 though the more common emtricitabine resistance seemed to have no effect on the combination regimen PrEP efficacy in non-human primate challenge models.8 The development of antiretroviral resistance while on PrEP if infection does occur, seems to be higher for users of emtricitabine plus tenofovir disoproxil fumarate than for users of tenofovir disoproxil fumarate alone (20% vs 5% in the Partners PrEP study on ultra-deep sequencing).9 This risk can be mitigated through careful screening before PrEP initiation and reinitiation. However, results of modelling studies suggest that PrEP would account for less than 4% of antiretroviral resistance at a population level over 20 years, most of the resistance coming from inadequate treatment of HIV-infected patients.10 Cost-effectiveness models suggest that PrEP would be cost effective in the USA11 and in developing countries,12 if targeted to individuals at highest risk. Although costs remain high for both regimens in the USA and other high-income countries, prices are quite low where generics are available, and substantially lower than the cost of treatment, in any case. In view of Baeten and colleagues’ data, tenofovir disoproxil fumarate alone might be a reasonable option for PrEP if cost or access would otherwise eliminate PrEP as an option. Why, then, has PrEP uptake been so slow globally? The results of four trials have shown substantial PrEP efficacy, likely exceeding 90% when adherence is high. With 50000 new infections every year in the USA and 2·3 million globally, surely there are many people who would benefit from PrEP. Arguments against offering PrEP often focus on the best form of prevention, variously defined as condoms, treatment for HIVinfected individuals, or clean injection equipment. All three of these options are vital, but none has been or www.thelancet.com/infection Vol 14 November 2014
Comment
likely will be sufficient alone to stop new HIV infections. PrEP might not be a perfect solution, but it is certainly an exceedingly good one. We must find ways to deliver PrEP to at-risk populations globally. Otherwise, as Voltaire is also quoted as saying, “Every man is guilty of all the good he did not do.” Susan Buchbinder San Francisco Department of Public Health, San Francisco, CA, USA [email protected] I have conducted PrEP studies funded by the National Institutes of Health. Gilead has provided drug for some of the PrEP trials in which I have been involved. 1
2
3
Baeten JM, Donnell D, Mugo NR, et al, for the Partners PrEP Study Team. Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial. Lancet Infect Dis 2014; published online Oct 7. http://dx.doi.org/10.1016/S1473-3099(14)70937-5. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012; 367: 399–410. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363: 2587–99.
4
5 6
7
8
9
10
11
12
Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012; 367: 423–34. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med 2012; 367: 411–22. Marrazzo J, Ramjee G, Nair G, et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine, or vaginal tenofovir gel in the VOICE Study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections; Atlanta, GA, USA; March 3–6, 2013. 26LB (abtrs). Chan PA, Huang A, Kantor R. Low prevalence of transmitted K65R and other tenofovir resistance mutations across different HIV-1 subtypes: implications for pre-exposure prophylaxis. J Int AIDS Soc 2012; 15: 17701. Cong ME, Mitchell J, Sweeney E, et al. Prophylactic efficacy of oral emtricitabine and tenofovir disoproxil fumarate combination therapy against a tenofovir-resistant simian/human immunodeficiency virus containing the K65R mutation in macaques. J Infect Dis 2013; 208: 463–67. Lehman DA, Baeten J, McCoy C, et al. PrEP exposure and the risk of lowfrequency drug resistance. 21st Conference on Retroviruses and Opportunistic Infections; Boston, MA, USA; March 3–6, 2014. van de Vijver DA, Nichols BE, Abbas UL, et al. Preexposure prophylaxis will have a limited impact on HIV-1 drug resistance in sub-Saharan Africa: a comparison of mathematical models. AIDS 2013; 27: 2943–51. Kessler J, Myers JE, Nucifora KA, et al. Evaluating the impact of prioritization of antiretroviral pre-exposure prophylaxis in New York City. AIDS 2014: published online Sept 10. Nichols BE, Boucher CA, van Dijk JH, et al. Cost-effectiveness of preexposure prophylaxis (PrEP) in preventing HIV-1 infections in rural Zambia: a modeling study. PLoS One 2013; 8: e59549.
Because of shared routes of transmission, 5–25% of the 34 million people with HIV worldwide are coinfected with either hepatitis B virus (HBV), hepatitis C virus (HCV), or both,1 with the highest number of co-infections in low-income countries. The negative effect of HIV infection on the progression of HBV and HCV infection is well established, with high rates of viral persistence, higher hepatitis viral load, and a more rapid progression to liver fibrosis and hepatocellular carcinoma in HIV-positive patients.2 In high-income countries, hepatic disease is the third highest cause of death in people with HIV after AIDS-related mortality and non-AIDS cancer deaths3, and hepatocellular carcinoma causes a quarter of liver-related deaths.2 Because of the increasing availability of antiretroviral therapy and the high burden of viral hepatitis, chronic hepatitis and its consequences are expected to become a leading burden of disease in resource-limited countries, although the true prevalence and clinical evolution of liver disease in low-income and middleincome countries are still largely unknown. In highly endemic regions such as Africa and Asia, the prevalence of HBV is estimated to be as much as 8% (10–15% in www.thelancet.com/infection Vol 14 November 2014
some countries), and HBV infection mostly occurs early in life through vertical or child-to-child transmission; the effect of hepatocellular carcinoma is likely to be even greater than estimated, particularly in Asia where HBV genotype C is highly prevalent.4 The clinical effect of viral hepatitis infection on the natural history of HIV infection is unclear. Some evidence suggests that viral hepatitis increases the risk of mother-to-child-transmission of HIV, accelerates HIVdisease progression, increases HIV viral setpoint, and blunts the response to antiretroviral therapy, resulting in a smaller and slower CD4 cell increase than reported in people without HBV or HCV. In The Lancet Infectious Diseases, Zhang and colleagues5 provide a unique overview of survival, virological response, and immunological response to antiretroviral therapy in a huge cohort of Chinese HIVpositive patients also infected with HBV, HCV, or both. To our knowledge, this cohort is the largest addressing this subject, and the most extensive study of triple infection reported so far. Although the prevalence of HBV co-infection in China reported by Zhang and colleagues (8·7%) is lower than that provided in
Imaginechina/Corbis
Hepatitis virus and HIV interactions
Published Online October 8, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70853-9 See Articles page 1065
1025
