Expert Review of Anti-infective Therapy
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Antiretrovirals for HIV prevention: when should they be recommended? Maja Kiselinova, Ward De Spiegelaere, Chris Verhofstede, Steven FJ Callens & Linos Vandekerckhove To cite this article: Maja Kiselinova, Ward De Spiegelaere, Chris Verhofstede, Steven FJ Callens & Linos Vandekerckhove (2014) Antiretrovirals for HIV prevention: when should they be recommended?, Expert Review of Anti-infective Therapy, 12:4, 431-445 To link to this article: http://dx.doi.org/10.1586/14787210.2014.896739
Published online: 12 Mar 2014.
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Antiretrovirals for HIV prevention: when should they be recommended? Downloaded by [University of Wisconsin Oshkosh] at 12:58 10 November 2015
Expert Rev. Anti Infect. Ther. 12(4), 431–445 (2014)
Maja Kiselinova1, Ward De Spiegelaere1, Chris Verhofstede2, Steven FJ Callens3‡ and Linos Vandekerckhove*1,3‡ 1 Department of Internal Medicine, HIV Translational Research Unit (HTRU), Ghent University and Ghent University Hospital, Ghent, Belgium 2 Department of Clinical Chemistry, Microbiology and Immunology, AIDS Reference Laboratory (ARL), Ghent University, Ghent, Belgium 3 Department of Internal Medicine and Infectious Diseases, Ghent University Hospital, Ghent, Belgium *Author for correspondence: Tel.: +32 093 323 398 Fax: +32 093 323 841 [email protected] ‡
Authors contributed equally
informahealthcare.com
Since the introduction of the first antiretroviral agent for HIV treatment, information on antiretroviral therapy (ART) effectiveness has grown continuously. In recent years, there has also been a growth of interest in use of ART for the prevention of HIV transmission, either by reducing the infectivity of the infected person or by protecting the uninfected individuals from HIV acquisition. The purpose of this review is to summarize the body of evidence available for treatment as prevention and pre-exposure prophylaxis and their effectiveness in prevention of infection. In addition, our aim is to discuss the operational aspects of both prevention strategies and to provide commentary for future HIV prevention programs. KEYWORDS: antiretroviral therapy • HIV-1 • pre-exposure prophylaxis • prevention • treatment as prevention
The prevention of HIV transmission mainly hinges on abstinence, faithfulness, reduction of sexual partners, male circumcision and consistent and correct use of condoms [1,2]. Although these prevention strategies had some success, they only had a limited impact on the annual total number of new HIV infections [3,4]. Concurrently, the introduction of combination antiretroviral therapy (cART) resulted in a dramatic drop of plasma viral load (VL) to undetectable levels (1000 copies/ml. The results suggested that HIV heterosexual transmission is a function of the viral load, where ART use may play a role in lowering transmission
[31]
Zambia, Rwanda
PS
Serodiscordant couples
2993
To assess effect of ART provision in Serodiscordant couples
94% reduction in HIV transmission was observed when cART was administered and thus provided guidelines for ART incorporation with biobehavioral studies
[32]
ART: Antiretroviral therapy; CVL: community viral load; PS: Prospective study; RS: Retrospective study; RTC: Randomized controlled trial.
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Antiretrovirals for HIV prevention
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Table 1. Treatment as prevention studies for HIV-1 prevention (cont.). Study location
Type of study and design
Population
Size
Aim
Results
Ref.
San Francisco
Cross-section period analysis and longitudinal period analysis
HIV-positive people
12,512
The decrease in CVL in San Francisco from 2004–2008, corresponding with increased rates of HIV testing, ART coverage and effectiveness, and population-level virologic suppression, would be associated with a reduction in new HIV infections
Reduction in CVL (~37.5% from 2004 to 2008) were associated with a 45.6% decrease on new HIV diagnoses (from 798 to 434)
[8]
Canada
Prospective cohort study
HIV-positive people
2051
To examine the relation between plasma HIV-1 RNA concentrations in the community and HIV incidence among IDUs
The study reported HIV incidence of 2.49/100 person-years in IDU without HIV at study inclusion. Additionally, the increase of ART coverage (from 8.4 to 98.8%) was associated with decrease of CVL and a decrease in HIV incidence
[10]
Taiwan
observational study
HIV-positive people
4390
To determine the effect of the widespread use of ART on the evolution of the HIV epidemic
After implementing a policy for providing free access to highly active ART to all HIVinfected citizens, the HIV transmission rate decreased by 53% in Taiwan
[9]
South Africa
Prospective observational study
HIV noninfected
16,667
To observe individual seroconversions
The study reported a low HIV transmission rate in areas with high ART coverage (30–40% of all HIV infected people receiving ART). In this high coverage ART areas, HIV acquisition was 38% less likely to occur. Therefore, the study conclusion was that population-level reductions in the transmission of HIV can be achieved in nurse-led, devolved, public sector ART programs
[7]
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Ecological studies
ART: Antiretroviral therapy; CVL: community viral load; PS: Prospective study; RS: Retrospective study; RTC: Randomized controlled trial.
However, this body of data did not observe a decline in HIV transmission despite expanded cART coverage. Population-wide observational studies in France and Denmark observed a stagnation in HIV incidence with increase in HIV prevalence in MSM [20,47], which may have been explained by decrease in undiagnosed HIV cases and a trend for earlier diagnosis [47]. Moreover, in The Netherlands, the UK and Australia, an increase of yearly HIV diagnoses in MSM has been observed, despite wide-spread cART coverage in these countries [48–51]. informahealthcare.com
This stable or slowly increasing incidence of HIV in MSM in some countries where widespread use of ART has been established highlights the concern that not enough is known about TasP use in at-risk population [11]. Furthermore, reducing HIV incidence among IDUs has been a focus point in the last years because IDUs represent a high-risk population for HIV transmission [45,52]. In addition, the ability of ART to prevent HIV transmission in IDUs has not been fully demonstrated yet. The biggest concern are IDUs with high-risk injecting behaviors, 435
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Kiselinova, De Spiegelaere, Verhofstede & Vandekerckhove
i.e., frequent needle sharing [45,53]. The effectiveness of TasP in these populations should be studied longitudinally to provide more data that are urgently needed. These data will further enhance strategies for combining targeted testing with an early cART intervention to reach hidden, high-risk populations with HIV testing, counseling and linkages to treatment and care [54,55]. Recent modeling data suggested that the priority of HIV prevention programs should be focused on the expansion of ART coverage and afterward more affordable VL monitoring should follow [56].
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Operational implications for TasP use
The evidence of TasP effectiveness is the strongest for serodiscordant couples, and there are complementary findings for MSM [14,15]. Additionally, data from British Columbia for TasP effectiveness in IDUs are available as well (TABLE 1) [10,52]. However, prescription of cART is not without risk. Suboptimal therapy adherence can lead to drug resistance development or to an increase in sexual risk behavior [57]. Hence, it will be crucial to assess the impact of TasP on adherence, viral resistance, therapy failure and sexual behavior. Adherence to cART medication is the most important patient-enabled predictor of treatment success. Nonadherence to cART has been shown to range between 33 and 88% in general adult populations [58]. Suboptimal treatment and not sustained treatment adherence can lead to prevention failure from HIV transmission. The significance of low-level viremia and the effect of suboptimal treatment in onward HIV transmission is still under debate. In addition, depending on the treatment combination, different risk levels of developing drug resistance exists. For example, a substantial risk of failed viral suppression is associated with HIV regimens containing an unboosted protease inhibitor with treatment adherence lower than 95% [59,60]. The suboptimal treatment can lead to the development and eventual transmission of drug-resistant HIV variants [40,61]. Widespread drug resistance will certainly diminish or even abolish any effect of cART on HIV transmission. A diverse range of factors influences cART adherence such as concerns about therapy side effects, perception of personal need of cART as a regimen, a wide range of psychological issues, socioeconomic aspects or personal confidence in adherence ability [58,60]. Therefore, the prescribed TasP should have several characteristics to be highly effective: it should be easily applicable with limited adverse effects and it should consistently suppress the HIV load in male and female genital compartments [62]. The latter point may be essential because nonoptimal viral suppression in the genital tract can allow the shedding of viral variants regardless of cART. The transmission potential of these HIV variants has not been elucidated yet [63]. The number of HIV variants and the efficiency of transmission differs between populations, being higher in MSM and IDUs compared with serodiscordant heterosexual couples [62,64]. Constant high adherence levels of optimal treatment are required to further reduce or totally eliminate failed viral suppression, and the possibility of shedding viral variants causing HIV transmission. 436
There is an ongoing debate whether regular or sporadic events of high-risk sexual behavior in patients on treatment can affect the onward transmission of HIV. To this day, a decrease in condom use has been documented in the framework of TasP, especially among MSM [65]. In addition, increases in high-risk sexual behaviors were noticed after 2008 and the release of the Swiss Statement. Increased sexual risk behaviors constitute a concern as it might offset the effect of TasP [57]. A recently published study from 2013 found a small, but significant proportion of cART-treated patients with HIV viremia and well-documented resistant HIV strains that continued to engage in high-risk sexual behaviors [66]. Because of the different effect that ART use can have on a person, it is recommended that the new prevention strategies should include biobehavioral HIV interventions that will encompass a diverse range of social aspects along with risk-reduction counseling, linkage to care and treatment, followed by provision of support. In addition, several treatment aspects should be carefully addressed including therapy combination and dosing. More specifically, the time and event-driven dosing are to be studied, as the HPTN 067 study in MSM and heterosexual women reported that different cART doses and time constraints has different effects and is differently perceived by the individuals [67]. Modeling data suggest that current cART coverage in South Africa contributes to the reduction in HIV incidence [7]. Hence, in developing countries, earlier cART will have to be incrementally introduced and monitored for programmatic, clinical and funding reasons. Successful TasP will require higher levels of HIV testing, with enhanced linkage to and retention in care, but will also require access to treatment with adherence support provision, and new ways to monitor therapy coverage and impact [68]. Because of the beneficial effects observed by TasP as a form of early treatment for individual patients and as a contribution to HIV prevention, in general, the question rises whether we need to wait for further randomized controlled trials (RTC) to motivate wide range early cART administration to prevent secondary transmission. Especially, because the individual benefits of early administered cART have been demonstrated to improve survival combined with decreased viral burden and viral diversity [69,70]. More data that will add to the knowledge of the benefits from early administered cART and clinical management of HIV-positive people will be available when the findings of the START and ANRS 12 136 Temprano studies will be published [71]. Pre-exposure prophylaxis
Provision of PrEP to reduce risks of acquiring certain infectious disease (e.g., malaria) is well established and has been used for many decades. It was recently proposed that PrEP can reduce transmission risk of HIV [15,72]. The first proof of concept of PrEP effectiveness came from the CAPRISA 004 trial, where the use of 1% tenofovir gel (applied vaginally and used twotimes; 12 h before and after sexual intercourse) resulted in a Expert Rev. Anti Infect. Ther. 12(4), (2014)
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39% reduction of HIV acquisition [73]. After CAPRISA, the landmark clinical trials for the use of oral PrEP followed. These trials were the iPrEx, TDF2 and Partners for PrEP studies, all of which showed a reduction of HIV acquisition among PrEP users in different populations and within different settings [15,72,74,75]. These trials aimed to evaluate the effectiveness, safety and tolerability of oral and/or topical PrEP, to assess therapy adherence and any changes in sexual behavior (TABLE 2). In general, HIV PrEP studies have been performed in different risk populations and within different settings. During past years, HIV serodiscordant couples were the priority group for risk reduction programs. However, the latest PrEP research focus on the MSM population as these constitute a large group, representing the majority of prevalent and incident HIV cases [3]. Conversely, only one study involving IDUs has been published so far [75]. More PrEP studies involving IDUs, MSM, female sex workers (FSW) and serodiscordant couples are being undertaken [76]. Other populations including prisoners, internally displaced people, refugees, etc. are currently not represented in these prevention studies. Future studies should focus on these groups as they are also considered among the most-at-risk populations (MARPs). The effectiveness of PrEP differs between published studies, and this high variety of PrEP efficacy depends on adherence or specific populations. Suboptimal adherence decreases or even completely abolishes PrEP effectiveness. A drop of protective effects was observed from 75% in studies with high adherence (Partners PrEP study) to only 6% in those where low adherence was reported (FEM PrEP study) [15,72–75,77]. As mentioned before, most current data are derived from PrEP use in serodiscordant heterosexual couples, followed by studies involving MSM and transgender women, and only one published study (Bangkok study) involved IDU (TABLE 2) [15,72–75]. Hereafter, we will focus on PrEP studies done in different at-risk populations. PrEP in heterosexual individuals & discordant couples
Several studies involving serodiscordant couples have been reported (TABLE 2). A 63% reduction of HIV acquisition was registered in the TDF2 study in Botswana, which consisted of a randomized trial involving daily use of Truvada (TDF/ FTC) [72]. Next, a randomized, multinational trial involving HIV serodiscordant couples in Kenya and Uganda, the Partners PrEP study, reported that daily PrEP intake of either TDF alone or combined as TDF/FTC reduced the risk of HIV acquisition by 67 and 75%, respectively [74]. In addition, people with detectable plasma TDF levels, that is, high PrEP adherence, were associated with 86 and 90% reduction in HIV acquisition, for the TDF and TDF/FTC groups, respectively [74]. Recently, intermittent PrEP was found to be acceptable, safe and well tolerated in a study where both daily and intermittent PrEP regimens among HIV serodiscordant couples were evaluated [78]. In addition, this study reported high adherence levels in both groups, but somewhat higher adherence was found in the group assigned with daily PrEP regimen [78]. Two PrEP interventions (VOICE study and FEM-PrEP trial) involving African women, heterosexual women and FSW informahealthcare.com
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have been conducted [77,79]. Both PrEP trials were discontinued because HIV incidence was similar among all arms including the placebo control. The VOICE study was discontinued because a high HIV incidence of 5.9% was observed among all women with no difference in the HIV incidence rate compared with the placebo arm. The high incidence rate was likely to be a result of decreased ART adherence rates, especially in unmarried women under the age of 25 years [79]. The FEM-PrEP trial was discontinued because an equal number of HIV infections were observed in both treatment and placebo arms. Drug-level analyses showed that adherence levels were very low, as less than 40% of the women had taken any drug in the 48 h before a drug test, and only 1/4 of women had taken their pills daily [77]. It is theoretically possible that individuals using PrEP may feel protected and abandon condom use and other protective measure. Interestingly, to this date, none of the oral or topical PrEP trials in heterosexual serodiscordant couples has observed increased HIV risk behavior that would suggest risk compensation [15,72,74,77,78,80]. PrEP in MSM
Diverse biological and epidemiological sources influence MSM susceptibility for HIV acquisition [65]. Receptive anal intercourse is shown to be the most efficient way for HIV transmission [81]. Other factors associated with an increased risk of HIV transmission are partners having other sexually transmitted diseases, being uncircumcised, frequently changing sexual partners or engaging in group sex, etc. [65,81]. Hence, the MSM population has been extensively involved in HIV prevention studies. The first report of PrEP efficacy in MSM and transgender women was the iPrEx study of 2010, demonstrating an overall 44% of transmission risk reduction when daily oral combination of TDF/FTC was used [15]. However, a reduction of only 32% of HIV incidence was observed in cases with low adherence ( or = 200 cells/microl. AIDS 2006;20(8):1117-23 Cu-Uvin S, Caliendo AM, Reinert S, et al. Effect of highly active antiretroviral therapy on cervicovaginal HIV-1 RNA. AIDS 2000; 14(4):415-21
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The authors estimated that the cost-effective prevention program with
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ISSN: 1478-7210 (Print) 1744-8336 (Online) Journal homepage: http://www.tandfonline.com/loi/ierz20
Antiretrovirals for HIV prevention: when should they be recommended? Maja Kiselinova, Ward De Spiegelaere, Chris Verhofstede, Steven FJ Callens & Linos Vandekerckhove To cite this article: Maja Kiselinova, Ward De Spiegelaere, Chris Verhofstede, Steven FJ Callens & Linos Vandekerckhove (2014) Antiretrovirals for HIV prevention: when should they be recommended?, Expert Review of Anti-infective Therapy, 12:4, 431-445 To link to this article: http://dx.doi.org/10.1586/14787210.2014.896739
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Antiretrovirals for HIV prevention: when should they be recommended? Downloaded by [University of Wisconsin Oshkosh] at 12:58 10 November 2015
Expert Rev. Anti Infect. Ther. 12(4), 431–445 (2014)
Maja Kiselinova1, Ward De Spiegelaere1, Chris Verhofstede2, Steven FJ Callens3‡ and Linos Vandekerckhove*1,3‡ 1 Department of Internal Medicine, HIV Translational Research Unit (HTRU), Ghent University and Ghent University Hospital, Ghent, Belgium 2 Department of Clinical Chemistry, Microbiology and Immunology, AIDS Reference Laboratory (ARL), Ghent University, Ghent, Belgium 3 Department of Internal Medicine and Infectious Diseases, Ghent University Hospital, Ghent, Belgium *Author for correspondence: Tel.: +32 093 323 398 Fax: +32 093 323 841 [email protected] ‡
Authors contributed equally
informahealthcare.com
Since the introduction of the first antiretroviral agent for HIV treatment, information on antiretroviral therapy (ART) effectiveness has grown continuously. In recent years, there has also been a growth of interest in use of ART for the prevention of HIV transmission, either by reducing the infectivity of the infected person or by protecting the uninfected individuals from HIV acquisition. The purpose of this review is to summarize the body of evidence available for treatment as prevention and pre-exposure prophylaxis and their effectiveness in prevention of infection. In addition, our aim is to discuss the operational aspects of both prevention strategies and to provide commentary for future HIV prevention programs. KEYWORDS: antiretroviral therapy • HIV-1 • pre-exposure prophylaxis • prevention • treatment as prevention
The prevention of HIV transmission mainly hinges on abstinence, faithfulness, reduction of sexual partners, male circumcision and consistent and correct use of condoms [1,2]. Although these prevention strategies had some success, they only had a limited impact on the annual total number of new HIV infections [3,4]. Concurrently, the introduction of combination antiretroviral therapy (cART) resulted in a dramatic drop of plasma viral load (VL) to undetectable levels (1000 copies/ml. The results suggested that HIV heterosexual transmission is a function of the viral load, where ART use may play a role in lowering transmission
[31]
Zambia, Rwanda
PS
Serodiscordant couples
2993
To assess effect of ART provision in Serodiscordant couples
94% reduction in HIV transmission was observed when cART was administered and thus provided guidelines for ART incorporation with biobehavioral studies
[32]
ART: Antiretroviral therapy; CVL: community viral load; PS: Prospective study; RS: Retrospective study; RTC: Randomized controlled trial.
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Table 1. Treatment as prevention studies for HIV-1 prevention (cont.). Study location
Type of study and design
Population
Size
Aim
Results
Ref.
San Francisco
Cross-section period analysis and longitudinal period analysis
HIV-positive people
12,512
The decrease in CVL in San Francisco from 2004–2008, corresponding with increased rates of HIV testing, ART coverage and effectiveness, and population-level virologic suppression, would be associated with a reduction in new HIV infections
Reduction in CVL (~37.5% from 2004 to 2008) were associated with a 45.6% decrease on new HIV diagnoses (from 798 to 434)
[8]
Canada
Prospective cohort study
HIV-positive people
2051
To examine the relation between plasma HIV-1 RNA concentrations in the community and HIV incidence among IDUs
The study reported HIV incidence of 2.49/100 person-years in IDU without HIV at study inclusion. Additionally, the increase of ART coverage (from 8.4 to 98.8%) was associated with decrease of CVL and a decrease in HIV incidence
[10]
Taiwan
observational study
HIV-positive people
4390
To determine the effect of the widespread use of ART on the evolution of the HIV epidemic
After implementing a policy for providing free access to highly active ART to all HIVinfected citizens, the HIV transmission rate decreased by 53% in Taiwan
[9]
South Africa
Prospective observational study
HIV noninfected
16,667
To observe individual seroconversions
The study reported a low HIV transmission rate in areas with high ART coverage (30–40% of all HIV infected people receiving ART). In this high coverage ART areas, HIV acquisition was 38% less likely to occur. Therefore, the study conclusion was that population-level reductions in the transmission of HIV can be achieved in nurse-led, devolved, public sector ART programs
[7]
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Ecological studies
ART: Antiretroviral therapy; CVL: community viral load; PS: Prospective study; RS: Retrospective study; RTC: Randomized controlled trial.
However, this body of data did not observe a decline in HIV transmission despite expanded cART coverage. Population-wide observational studies in France and Denmark observed a stagnation in HIV incidence with increase in HIV prevalence in MSM [20,47], which may have been explained by decrease in undiagnosed HIV cases and a trend for earlier diagnosis [47]. Moreover, in The Netherlands, the UK and Australia, an increase of yearly HIV diagnoses in MSM has been observed, despite wide-spread cART coverage in these countries [48–51]. informahealthcare.com
This stable or slowly increasing incidence of HIV in MSM in some countries where widespread use of ART has been established highlights the concern that not enough is known about TasP use in at-risk population [11]. Furthermore, reducing HIV incidence among IDUs has been a focus point in the last years because IDUs represent a high-risk population for HIV transmission [45,52]. In addition, the ability of ART to prevent HIV transmission in IDUs has not been fully demonstrated yet. The biggest concern are IDUs with high-risk injecting behaviors, 435
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i.e., frequent needle sharing [45,53]. The effectiveness of TasP in these populations should be studied longitudinally to provide more data that are urgently needed. These data will further enhance strategies for combining targeted testing with an early cART intervention to reach hidden, high-risk populations with HIV testing, counseling and linkages to treatment and care [54,55]. Recent modeling data suggested that the priority of HIV prevention programs should be focused on the expansion of ART coverage and afterward more affordable VL monitoring should follow [56].
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Operational implications for TasP use
The evidence of TasP effectiveness is the strongest for serodiscordant couples, and there are complementary findings for MSM [14,15]. Additionally, data from British Columbia for TasP effectiveness in IDUs are available as well (TABLE 1) [10,52]. However, prescription of cART is not without risk. Suboptimal therapy adherence can lead to drug resistance development or to an increase in sexual risk behavior [57]. Hence, it will be crucial to assess the impact of TasP on adherence, viral resistance, therapy failure and sexual behavior. Adherence to cART medication is the most important patient-enabled predictor of treatment success. Nonadherence to cART has been shown to range between 33 and 88% in general adult populations [58]. Suboptimal treatment and not sustained treatment adherence can lead to prevention failure from HIV transmission. The significance of low-level viremia and the effect of suboptimal treatment in onward HIV transmission is still under debate. In addition, depending on the treatment combination, different risk levels of developing drug resistance exists. For example, a substantial risk of failed viral suppression is associated with HIV regimens containing an unboosted protease inhibitor with treatment adherence lower than 95% [59,60]. The suboptimal treatment can lead to the development and eventual transmission of drug-resistant HIV variants [40,61]. Widespread drug resistance will certainly diminish or even abolish any effect of cART on HIV transmission. A diverse range of factors influences cART adherence such as concerns about therapy side effects, perception of personal need of cART as a regimen, a wide range of psychological issues, socioeconomic aspects or personal confidence in adherence ability [58,60]. Therefore, the prescribed TasP should have several characteristics to be highly effective: it should be easily applicable with limited adverse effects and it should consistently suppress the HIV load in male and female genital compartments [62]. The latter point may be essential because nonoptimal viral suppression in the genital tract can allow the shedding of viral variants regardless of cART. The transmission potential of these HIV variants has not been elucidated yet [63]. The number of HIV variants and the efficiency of transmission differs between populations, being higher in MSM and IDUs compared with serodiscordant heterosexual couples [62,64]. Constant high adherence levels of optimal treatment are required to further reduce or totally eliminate failed viral suppression, and the possibility of shedding viral variants causing HIV transmission. 436
There is an ongoing debate whether regular or sporadic events of high-risk sexual behavior in patients on treatment can affect the onward transmission of HIV. To this day, a decrease in condom use has been documented in the framework of TasP, especially among MSM [65]. In addition, increases in high-risk sexual behaviors were noticed after 2008 and the release of the Swiss Statement. Increased sexual risk behaviors constitute a concern as it might offset the effect of TasP [57]. A recently published study from 2013 found a small, but significant proportion of cART-treated patients with HIV viremia and well-documented resistant HIV strains that continued to engage in high-risk sexual behaviors [66]. Because of the different effect that ART use can have on a person, it is recommended that the new prevention strategies should include biobehavioral HIV interventions that will encompass a diverse range of social aspects along with risk-reduction counseling, linkage to care and treatment, followed by provision of support. In addition, several treatment aspects should be carefully addressed including therapy combination and dosing. More specifically, the time and event-driven dosing are to be studied, as the HPTN 067 study in MSM and heterosexual women reported that different cART doses and time constraints has different effects and is differently perceived by the individuals [67]. Modeling data suggest that current cART coverage in South Africa contributes to the reduction in HIV incidence [7]. Hence, in developing countries, earlier cART will have to be incrementally introduced and monitored for programmatic, clinical and funding reasons. Successful TasP will require higher levels of HIV testing, with enhanced linkage to and retention in care, but will also require access to treatment with adherence support provision, and new ways to monitor therapy coverage and impact [68]. Because of the beneficial effects observed by TasP as a form of early treatment for individual patients and as a contribution to HIV prevention, in general, the question rises whether we need to wait for further randomized controlled trials (RTC) to motivate wide range early cART administration to prevent secondary transmission. Especially, because the individual benefits of early administered cART have been demonstrated to improve survival combined with decreased viral burden and viral diversity [69,70]. More data that will add to the knowledge of the benefits from early administered cART and clinical management of HIV-positive people will be available when the findings of the START and ANRS 12 136 Temprano studies will be published [71]. Pre-exposure prophylaxis
Provision of PrEP to reduce risks of acquiring certain infectious disease (e.g., malaria) is well established and has been used for many decades. It was recently proposed that PrEP can reduce transmission risk of HIV [15,72]. The first proof of concept of PrEP effectiveness came from the CAPRISA 004 trial, where the use of 1% tenofovir gel (applied vaginally and used twotimes; 12 h before and after sexual intercourse) resulted in a Expert Rev. Anti Infect. Ther. 12(4), (2014)
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39% reduction of HIV acquisition [73]. After CAPRISA, the landmark clinical trials for the use of oral PrEP followed. These trials were the iPrEx, TDF2 and Partners for PrEP studies, all of which showed a reduction of HIV acquisition among PrEP users in different populations and within different settings [15,72,74,75]. These trials aimed to evaluate the effectiveness, safety and tolerability of oral and/or topical PrEP, to assess therapy adherence and any changes in sexual behavior (TABLE 2). In general, HIV PrEP studies have been performed in different risk populations and within different settings. During past years, HIV serodiscordant couples were the priority group for risk reduction programs. However, the latest PrEP research focus on the MSM population as these constitute a large group, representing the majority of prevalent and incident HIV cases [3]. Conversely, only one study involving IDUs has been published so far [75]. More PrEP studies involving IDUs, MSM, female sex workers (FSW) and serodiscordant couples are being undertaken [76]. Other populations including prisoners, internally displaced people, refugees, etc. are currently not represented in these prevention studies. Future studies should focus on these groups as they are also considered among the most-at-risk populations (MARPs). The effectiveness of PrEP differs between published studies, and this high variety of PrEP efficacy depends on adherence or specific populations. Suboptimal adherence decreases or even completely abolishes PrEP effectiveness. A drop of protective effects was observed from 75% in studies with high adherence (Partners PrEP study) to only 6% in those where low adherence was reported (FEM PrEP study) [15,72–75,77]. As mentioned before, most current data are derived from PrEP use in serodiscordant heterosexual couples, followed by studies involving MSM and transgender women, and only one published study (Bangkok study) involved IDU (TABLE 2) [15,72–75]. Hereafter, we will focus on PrEP studies done in different at-risk populations. PrEP in heterosexual individuals & discordant couples
Several studies involving serodiscordant couples have been reported (TABLE 2). A 63% reduction of HIV acquisition was registered in the TDF2 study in Botswana, which consisted of a randomized trial involving daily use of Truvada (TDF/ FTC) [72]. Next, a randomized, multinational trial involving HIV serodiscordant couples in Kenya and Uganda, the Partners PrEP study, reported that daily PrEP intake of either TDF alone or combined as TDF/FTC reduced the risk of HIV acquisition by 67 and 75%, respectively [74]. In addition, people with detectable plasma TDF levels, that is, high PrEP adherence, were associated with 86 and 90% reduction in HIV acquisition, for the TDF and TDF/FTC groups, respectively [74]. Recently, intermittent PrEP was found to be acceptable, safe and well tolerated in a study where both daily and intermittent PrEP regimens among HIV serodiscordant couples were evaluated [78]. In addition, this study reported high adherence levels in both groups, but somewhat higher adherence was found in the group assigned with daily PrEP regimen [78]. Two PrEP interventions (VOICE study and FEM-PrEP trial) involving African women, heterosexual women and FSW informahealthcare.com
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have been conducted [77,79]. Both PrEP trials were discontinued because HIV incidence was similar among all arms including the placebo control. The VOICE study was discontinued because a high HIV incidence of 5.9% was observed among all women with no difference in the HIV incidence rate compared with the placebo arm. The high incidence rate was likely to be a result of decreased ART adherence rates, especially in unmarried women under the age of 25 years [79]. The FEM-PrEP trial was discontinued because an equal number of HIV infections were observed in both treatment and placebo arms. Drug-level analyses showed that adherence levels were very low, as less than 40% of the women had taken any drug in the 48 h before a drug test, and only 1/4 of women had taken their pills daily [77]. It is theoretically possible that individuals using PrEP may feel protected and abandon condom use and other protective measure. Interestingly, to this date, none of the oral or topical PrEP trials in heterosexual serodiscordant couples has observed increased HIV risk behavior that would suggest risk compensation [15,72,74,77,78,80]. PrEP in MSM
Diverse biological and epidemiological sources influence MSM susceptibility for HIV acquisition [65]. Receptive anal intercourse is shown to be the most efficient way for HIV transmission [81]. Other factors associated with an increased risk of HIV transmission are partners having other sexually transmitted diseases, being uncircumcised, frequently changing sexual partners or engaging in group sex, etc. [65,81]. Hence, the MSM population has been extensively involved in HIV prevention studies. The first report of PrEP efficacy in MSM and transgender women was the iPrEx study of 2010, demonstrating an overall 44% of transmission risk reduction when daily oral combination of TDF/FTC was used [15]. However, a reduction of only 32% of HIV incidence was observed in cases with low adherence ( or = 200 cells/microl. AIDS 2006;20(8):1117-23 Cu-Uvin S, Caliendo AM, Reinert S, et al. Effect of highly active antiretroviral therapy on cervicovaginal HIV-1 RNA. AIDS 2000; 14(4):415-21
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