Long-Acting Injection and Implant Preferences and Trade-Offs for HIV Prevention Among South African Male Youth : JAIDS Journal of Acquired Immune Deficiency Syndromes

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Prevention Research

Long-Acting Injection and Implant Preferences and Trade-Offs for HIV Prevention Among South African Male Youth

Montgomery, Elizabeth T. PhDa; Browne, Erica N. MSa; Atujuna, Millicent PhDb; Boeri, Marco PhDc; Mansfield, Carol PhDb; Sindelo, Siyaxolisa BAd; Hartmann, Miriam MPHa; Ndwayana, Sheily BAd; Bekker, Linda-Gail PhD, MDd; Minnis, Alexandra M. PhDa

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: July 1, 2021 - Volume 87 - Issue 3 - p 928-936
doi: 10.1097/QAI.0000000000002670

Abstract

INTRODUCTION

Oral pre-exposure prophylaxis (PrEP) is a highly efficacious biomedical HIV prevention method; however, its effectiveness has been challenged by a daily dosing regimen negatively impacting adherence.1 Long-acting (LA) PrEP delivered by implant or injection addresses user preferences for simplicity, discretion, and longer dose duration.2 Currently, there are several PrEP implants in preclinical development, and the first human implant study (with women) presented promising findings in the summer of 2019.3–5 Injectable formulations of the integrase inhibitor cabotegravir, used as PrEP, and tested with cisgender men and transgender women (HPTN 083), and cisgender women (HPTN 084) announced superiority over oral PrEP in July and October 2020, respectively.6,7 Collectively, these long-acting delivery platforms offer a potential variety of future HIV prevention options for men and women. To date, acceptability for injectables among men who have sex with men (MSM) and women has been high,8 although attitudes of novel long-acting delivery formulations with male non-MSM end users have been limited.9

In sub-Saharan Africa, and South Africa specifically, the primary mode of HIV transmission is through heterosexual sex; however, most HIV prevention efforts do not successfully address heterosexual men's needs and their critical role in the cycle of HIV transmission.10 MSM constitute a key population for HIV prevention efforts,11 and have high HIV incidence in urban areas, and prevalence estimates of 49.5% in greater Johannesburg, 25.5% in Cape Town, and 27.5% in Durban.12–16 Thus, in South Africa, HIV prevalence among both MSM and non-MSM is high and increases with age, resulting in one-quarter (23.7%) of all men aged 35–39 years estimated as HIV positive.17 Unlike women of childbearing age, many men do not have regular interaction with the health care system and are less likely to engage in HIV prevention or care.18 Stigma and discrimination, particularly for MSM, further inhibit the use of HIV prevention services.19 Long-acting methods present an opportunity to potentially increase men's engagement in HIV prevention in this setting.

We conducted a discrete choice experiment (DCE) among youth aged 18–24 in Cape Town to explore attitudes toward and preferences for LA injectables and implants for HIV prevention. Using random parameters logit (RPL) modeling, youth were found to have a strong preference for a longer dosing duration, and we identified some differences in preference between male and female subgroups within other attributes presented.20 In the current study, we focused on preferences among male youth and used multiple techniques to understand potential market segments and shifts in preference share simulations for LA-PrEP. These analyses contribute insight into the varying preferences among groups of young men in South Africa for LA injections and implants and provide a stepping stone toward further integration of these essential populations of African men into HIV prevention.

METHODS

Study Design and Setting

Our DCE was implemented in several communities in and around Cape Town City Centre in 2017–2019. A detailed description of our full study sample, that also included female youth, sampling methods, and results of a conjoint analysis, has been published elsewhere.20 In brief, we used population-based representative sampling in 2 townships, Nyanga and Masiphumelele, to recruit youth meeting the eligibility criteria of being aged 18–24, HIV prevention research naïve, and residing in the sampled residential plot and to gather general opinions about long-acting HIV prevention method characteristics. MSM were recruited using a combination of respondent-driven sampling and convenience sampling approaches. During this study, PrEP was available only to key population groups, which included MSM, and MSM with PrEP experience were allowed to enroll.

Procedures

After recruitment, participants presented at one of the community-based research sites and were shown a 4-minute video about PrEP: (https://vimeo.com/manage/222758306/general), to explain what PrEP was and to describe the study's purpose. After the video, interested participants completed an informed consent process and a tablet-based questionnaire. The questionnaire included 9 DCE choice questions, followed by a set of questions which directly assessed preferences, as well as a set of attitudinal, behavioral, and sociodemographic questions. The DCE survey instrument was developed following Good Research Practices for conjoint analysis.21 Formative research was used to guide selection of 5 attributes to describe the LA-PrEP products: product formulation, dosing or how long the product lasts, where the product would be available, soreness from procedure, and location on the body of injection/implant. Choice sets were made up of 2 hypothetical products characterized by the 5 product attributes (Fig. 1). Each attribute had between 2 and 4 levels of variation, and all attribute levels were described with text and illustration. The DCE began with educational descriptions of the 5 product characteristics that would be explored during the survey. After this, participants were handed the tablet to self-administer, with assistance as needed, until the choice set section was completed. A set of behavioral and attitudinal questions, including some that directly elicited product preferences, were subsequently administered by the interviewer in English or Xhosa.

F1
FIGURE 1.:
Attributes and levels presented in DCE survey (reproduced from Minnis et al).20

For their time and transport costs, participants received a minor payment ($7) approved by the Human Research Ethics Committee at the University of Cape Town. The human research ethics committee also reviewed and approved the study protocol and all data collection documents (REF number 751/2015).

F2
FIGURE 2.:
Normalized preferences weights for attributes of a long-acting PrEP product, per latent class (N = 406). Positive weights indicate greater preference, and negative weights indicate less preference relative to other attribute levels evaluated.

Analysis

Sample characteristics were summarized and compared by the sexual orientation subgroup as MSM vs. men who have sex with women only (MSW) (only) using χ2 tests for categorical or Wilcoxon signed-rank tests for continuous measures. Direct assessments of preference (ie, importance of individual product characteristics and product use disclosure considerations) were summarized and compared by sexual orientation with χ2 tests. We used a latent class model (LCM) to analyze choice data from the DCE to explore potential heterogeneity of preferences among men.22,23 The LCM assumes that there are distinct classes (segments of the sample whereby the preferences among members of the same class are identical but different from other classes). The classification for each individual is unknown, but membership probabilities are estimated. The number of classes was determined by best model fit; a series of LCMs were estimated with increasing number of classes (up to 5), and the optimal model was selected based on minimum Bayesian information criterion and Akaike information criterion. All attributes were considered categorical and were effect coded, meaning zero indicated the average effect across all levels as opposed to the omitted level in dummy variable coding.24 Coefficients, therefore, represent normalized preference weights, where positive weights signify greater preference and negative weights indicate less preference relative to other attribute levels evaluated.

We explored how 10 sociodemographic and behavioral characteristics, informed by previous research, influenced the probability of class membership. All covariates were first modeled together, and only those with P ≤ 0.10 were included in the final estimated LCM. The final normalized preference weight coefficients from the LCM were then used to calculate preference shares for hypothetical product profiles created to simulate product development scenarios. The EM algorithm implemented in Stata with the lclogit2 procedure was used for LCMs. To draw statistical inferences, we used the lclogit2 estimates as starting values for the lclogitml2 to obtain the final maximum likelihood output with standard errors.25 All analyses were performed using Stata 15.0 (Statacorp, College Station, TX).

RESULTS

Study Population

The study enrolled 406 male youth aged 18–24 (mean 20.8, median 21 years). By design, nearly half (47%, n = 190) were MSM, and the remainder were MSW. The key characteristics of the population are presented in Table 1. MSM differed on several characteristics compared with MSW, including educational achievement, current partner status, and condom use at last sexual episode.

TABLE 1. - Sociodemographic and Behavioral Characteristics of Male Participants
MSW MSM Total P *
N % N % N %
Total 216 100 190 100 406 100
Sociodemographic factors
 Age, yr—median (IQR) 21 19–22 20 19–22 21 19–22 0.92
 Completed secondary school 112 52 133 70 245 60 <0.001
 Currently in school 85 39 110 58 195 48 <0.001
 Low educational attainment 59 27 25 13 84 21 <0.001
 Employed 84 39 53 28 137 34 0.009
 Food insecurity (past months) 50 23 69 36 119 29 0.004
 Fathered a child 35 16 8 4 43 11 <0.001
 Household crowding§ 45 21 10 5 55 14 <0.001
Behavioral factors
 Lifetime number of sex partners—median (IQR) 6 4–10 5 4–10 6 4–10 0.50
 Has primary partner 161 75 106 56 267 66 <0.001
  Primary partner has other partners 0.001
   Yes, know, or suspect 40 25 43 41 83 31
   No 63 39 20 19 83 31
   Do not know 58 36 43 41 101 38
 Multiple sex partners in past 3 mo 88 41 89 47 177 44 0.22
 Ever used condoms 199 95 184 98 383 97 0.15
 Condom use at last sex 119 55 131 69 250 62 0.01
HIV testing and status
 Ever tested for HIV 193 89 180 95 373 92 0.05
 HIV Status 0.001
  Negative 175 81 166 87 341 84
  Positive 4 2 11 6 15 4
  Unknown 37 17 13 7 50 12
 Worried about getting HIV in next 12 mo 0.44
  Extremely/very 55 26 41 22 96 24
  Somewhat/a little 86 40 87 46 173 43
  Not at all 75 35 62 33 137 34
Community of residence <0.001
 Masiphumelele 91 42 6 3 97 24
 Nyanga 115 53 40 21 155 38
 Others 10 5 144 76 154 38
iPrevent Study, Cape Town, South Africa, 2017–2018.
*P-value from the χ2 test or 2-sample Wilcoxon rank-sum test.
Less than secondary education and not currently in school.
“Sometimes” or “often” worried about not having enough food.
§More than 2 persons per room.
Proportion among those who have a primary partner.

Direct Elicitation of Preferences

Preferences are presented in Table 2. When asked directly about the importance of 6 select attributes of long-acting PrEP, most men reported several features to be “very important,” including perceived efficaciousness (94%), where one has to go to get it (88%), how often one has to use it (87%), and a product's removability if side effects experienced (85%). Product efficacy, which was defined as “how well it works,” was designated as the single most important attribute to over half the men (57%), in particular to MSM vs. MSW (64% vs 52%, P = 0.04). Privacy and disclosure were important to all (Table 2), although more MSW believed it was important to be able to use prevention methods without their partner knowing compared with MSM (46% vs. 27%, P < 0.001). Most (94%) reported a willingness to pay for a long-acting product, with half willing to pay at least 115 South African Rand (∼USD10).

TABLE 2. - Direct Elicitation of Preferences for Long-Acting Pre-exposure Prophylaxis Among Male Youth in Cape Town, South Africa (N = 406)
N %
Importance of attribute when selecting an HIV prevention product—“very important”
 How well it works to prevent HIV 380 94
 Where you have to go to get it 356 88
 How often you have to use it 353 87
 Removable if you experience side effects 346 85
 Where on your body its injected or inserted 239 59
 Can be used without your partner knowing 98 24
Most important attribute of 6 rated (top 3)
 How well it works to prevent HIV 234 58
 Removable if you experience side effects 61 15
 Where you have to go to get it 51 13
Importance of using HIV prevention without partner knowing
 Very important 76 19
 Somewhat important 76 19
 Not at all important 254 63
 If product could be used secretly, would tell partner anyway 316 78
Importance of using HIV prevention without household knowing
 Very important 108 27
 Somewhat important 88 22
 Not important 210 52
Cost willing to pay for a long-acting product (South African rand)—mean, median (IQR) 202, 115 50–200
 Not willing to pay 23 6
Implant characteristics
 Most preferred location for implant insertion (top 3)
  Inner upper arm 196 48
  Outer upper arm 94 23
  Inner thigh 39 10
 Least preferred location for implant insertion (top 3)
  Buttocks (“bum”) 206 51
  Inner thigh 60 15
  Lower back 36 9
 Biodegradability preference
  Dissolves over time 285 70
  Does not dissolve and would need to be removed 90 22
  No preference 9 2
  Neither—would not use an implant 22 5
Injection characteristics
 Most preferred location for injection (top 3)
  Outer upper arm 152 37
  Buttocks (“bum”) 122 30
  Inner upper arm 63 16
 Least preferred location for injection (top 3)
  Buttocks (“bum”) 175 43
  Inner thigh 52 13
  Inner upper arm 28 7

Preferences varied for where one would want an implant or injection to be inserted in the body (Table 2). The most popular preference for implant location, chosen by just under half, and more MSM (55%) than MSW (43%), was the inner upper arm. The next 2 most preferred locations were the outer upper arm (23%) and the inner thigh (10%). The least preferred location for an implant was the buttocks (“bum”) (51%) followed by the inner thigh (15%). The outer upper arm was selected as the most popular location (37%) for an injection, and there were no differences in location preference between MSM and MSW.

Biodegradable implants are under development, and we asked men whether they would prefer a product that dissolved over time or one that would need to be removed. Most (70%) expressed a preference for biodegradability. Of note, a small proportion of men (5%) indicated they would not use an implant.

Discrete Choice Modeling

Latent class analysis was used to identify preference segments in the study population. Based on several model fit indices, the 3 class model was considered optimal for these data, and for each class, the model estimated a set of preference weights (Table 3, see also Fig. 2, and the average membership probability.

TABLE 3. - Estimated Preference Shares, by Class, for Altering Long-Acting PrEP Scenarios
Scenario Product Product Description “Duration Dominant”
N = 46%
“Comprehensive Decision-Makers”
N = 36%
“Injection Dominant”
N = 17%
1 Product A Implant, 6-month duration, available at a clinic, moderate soreness, administered in the arm 0.79 0.63 0.05
Product B Injection (single), 2-month duration, available at a clinic, mild soreness, administered to the buttocks 0.21 0.37 0.95
2 Product A Implant, 12-month duration, available at a clinic, moderate soreness, administered in the arm 0.96 0.63 0.08
Product B Injection (single), 2-month duration, available at a clinic, mild soreness, administered to the buttocks 0.04 0.37 0.92
3 Product A Implant, 12-month duration, available at a clinic, moderate soreness, administered in the arm 0.80 0.53 0.05
Product B Injection (single), 6-month duration, available at a clinic, mild soreness, administered to the buttocks 0.20 0.47 0.95

The largest class, with an average membership probability of 46%, was defined predominantly by a significant preference for a longer-acting product and, hence, was deemed the “duration-dominant decision makers” segment. Respondents in this class also preferred mild over moderate soreness during the injection/implant procedure (P = 0.005), although duration was 12.5 times more important than the amount of anticipated soreness. The influence of product form on choice of a product was not as well defined, but trends suggested that men in this class most preferred a single injection (P = 0.05). Product insertion/injection site on the body and the location where product could be obtained were not influential to choice (P > 0.14) for this segment of male youth.

The second largest class membership probability (approximately 36%) was not particularly focused on any specific attribute, attaching similar relative importance to duration, soreness, product form, and location on the body. Hence, this segment was nicknamed “comprehensive decision makers.” On average, this class preferred mild to moderate soreness (P < 0.001), insertion in the arm over buttocks (P < 0.001), and disliked 2-month long products, with no difference in preference between products of 6-month and 12-month duration (P = 0.02). Members also preferred implants over 2 injections (P = 0.001). They did not show significant preference surrounding where the product was available (P = 0.16).

The third and smallest class (17%) was associated with preferences overwhelmingly focused on the product form. These men disliked implants and preferred injections (P < 0.0001), with slight preference for 1 over 2 injections (P = 0.05). As such, this segment was termed “injection-dominant decision-makers.” This class also had preference for longer duration products and opinions on where the product is available, but these opinions were significantly less important than the product form. The product form was 3.5 times as important as duration and nearly 5 times as important as the location where a product was made available. Men in this class preferred the product to be available at a pharmacy rather than a mobile clinic (P = 0.02) or health clinic (P = 0.06). Trends also suggested this class would prefer the product be offered at a community location rather than by a mobile clinic (P = 0.08).

To characterize class membership, we included 10 potential covariates in the class membership probability function of our LC model that had been pairwise tested for independent correlation. Three variables were found to be associated with class membership at the P < 0.10 level and were included in the final LC model: being <21 years of age, MSM, and having a partner who (potentially) has other partners (when asked if primary partner has other partners responded “yes” or “do not know”). The “comprehensive decision-makers” class was set as the referent. MSM had higher odds of being associated with the “injection-dominant” [odds ratio (OR) 2.2, 95% confidence interval (CI): 1.1 to 4.5; P = 0.03] and “duration-dominant” (OR 1.8, 95% CI: 1.0 to 3.3; P = 0.07) class. Male youth with a primary partner who has or may have other sex partners had lower odds of being associated with the “injection-dominant” class (OR 0.5, 95% CI: 0.2 to 0.9; P = 0.06) and those under 21 years old had lower odds of being associated with the “duration-dominant” class (OR 0.6, 95% CI: 0.3 to 1.0; P = 0.06).

Preference Shares

Preference shares were estimated with the preference weights of the final LCM to demonstrate how preferences for hypothetical product profiles within each class might shift when product attributes were changed (Table 3).

Scenario 1 represented the estimated share for Product A, an implant with a duration of 6 months (the likely minimum target duration for this technology), conferring moderate soreness, and being administered in the arm at a health clinic. This was compared with Product B, an injection-based product that had characteristics representative of the current regimen being tested in human trials: one injection administered to the buttocks at a health clinic every 2 months with mild soreness at the injection site. Comparing these products, the majority (93%) of “injection-dominant” men favored the injection. By contrast, most in the “duration-dominant” class (84%) and more than two-thirds of the “comprehensive decision-makers” class (66%) were estimated to choose the implant.

In scenario 2, we increased the duration of the implant to 12 months and kept all other product features the same as scenario 1. In response, more “duration-dominant” men were expected to choose the implant (96%). There was no significant shift in the choices of “injection-dominant” or “comprehensive decision-makers.”

For scenario 3, all characteristics were the same as in scenario 2 except the duration of the injections was increased from 2 to 6 months. In this scenario, the preferences among men in the “injection-dominant” and “duration-dominant” classes were similar to those in scenario 1. The “comprehensive decision-makers” group, however, was more divided, with nearly equal shares estimated to choose each product, suggesting that if the injection conferred at least 6 months of protection; this class would be as likely to choose a 12-month implant as a 6-month single injection.

DISCUSSION

Men, both MSM and MSW, in the HIV-endemic setting of South Africa are a critical end-user population for novel forms of long-acting PrEP. In this study, we aimed to explore interest in implants and injections and to understand which attributes of a LA product were important to different segments of male end users. We identified several key findings. First, young men expressed strong overall interest in long-acting HIV prevention methods. In the stated preference portion of the survey, only 5% said they would never use an implant. Second, 3 broad segments of male end-user preferences were evident and highlighted the attributes of most importance. Product form (implant vs. injection(s)) and product duration (2, 6, and 12 months) were the characteristics most important to overall preference for two-thirds of men, whereas for the substantial minority of men in the “comprehensive” group, a more holistic consideration of product characteristics was salient. Finally, when product attributes were altered in simulated scenarios of preference shares, an increase in product duration drove shifts in estimated preferences for other attributes. A sizeable proportion of men were estimated to hypothetically select an implant over an injection if the former offered 4 months or 6 months of additional protection—suggesting a preference and potential future demand for this novel technology among male users.

There is well-established global experience among women for use of implants26 and injections for contraception;27 however, there is extremely limited knowledge of implant use—for any indication—in men globally, and no known knowledge of implant use by men in South Africa. Implant products for a few different indications are available to male users, including delivery of buprenorphine to treat opioid dependence for a duration of 6 months, and a previously approved, but discontinued, product to treat prostate cancer, breast cancer, and endometriosis.28–32 Injections are also a new product in HIV prevention, and the concept of being injected is arguably familiar to men. In these data, we see evidence that a substantial proportion of men, predominantly represented in the “duration-dominant” and “comprehensive” classes, would choose an implant over the injection regimen being tested in current trials. These estimates offer some evidence to implant developers that their products could be acceptable to future end users. The external validity of DCE findings—linking hypothetical preferences to actual behavior—is unknown, although DCE reportedly offer fairly good predictions into what end users will choose to take up.33 That said, several other factors beyond these attributes will influence behavior, particularly in the context of HIV prevention for youth, and in resource-challenged circumstances.34 Consequently, these findings are encouraging, but several other product-agnostic social, cultural, or structural factors may influence future interest and demand for implants in an African setting.

Not everyone in this study wanted the same features of a long-acting HIV prevention method, highlighting the importance of identifying population segments. Research and utilization statistics with women in the fields of contraception and HIV prevention have demonstrated that users want choice35,36 and that when more options are available, coverage is expanded.37 Here, we report evidence that men also favor different options, and although preference shares showing an interest for implants is encouraging, it is likewise encouraging that many men favor injections, particularly in light of recent results demonstrating the superiority of cabotegravir injections (vs. oral PrEP) in men.38 Although suggestive of a trend, but inconclusive (P > 0.05), men who had partners with other partners, or of unknown fidelity, were more likely to favor the longer-acting implant—potentially because of enhanced risk perception. Similarly, younger men younger than 21 were less likely to be driven by product duration, perhaps because they were in sexual relationships of less consistent duration. A study of HIV prevention method preference among South African heterosexual men reported that 48% would favor LA PrEP compared with oral PrEP or condoms,39 suggesting both a demand for and potential future acceptability of LA methods, and also an interest in a diversity of approaches. Also of interest was that a substantial minority felt it was very important that a method could be used secretly and without the knowledge of a sexual partner or household member.

In this analysis, although almost a third seemed to evaluate multiple elements of a LA product, the product form, and duration drove preferences for most. These results echo the findings of our RPL modeling in a separate analysis among male and female youth from this cohort,20 and point to the importance of several structural and sociobehavioral considerations in the lives of young men. This study's formative research used qualitative methods to explore the context of HIV prevention with youth40,41 and reported that dosing duration is important because it is linked to clinic visits, which can be perceived as a burden, stigmatizing, and incongruent with some masculinity norms.42 As long-acting HIV treatment strategies43 are being considered for licensure and roll-out, important concomitant implementation issues such as innovative ways to deliver doses, for example, mobile shot clinics, and meet ongoing testing needs (eg, through self-testing) require exploration.

In this study, preferences among MSM vs. MSW varied somewhat. MSM were more likely to be in the “injection-dominant” class, who more likely to want to avoid implants. MSM may not inherently dislike the option of implants, but may simply be more comfortable and familiar with injections, and familiarity has been shown to drive acceptability preference in other analyses.44 Similarly, if MSM are already taking oral PrEP, they may be satisfied with their regimen or less concerned about regular clinic visits. MSM preferences in our RPL modeling similarly highlighted that MSM preferred injections over implants, and that MSM were keen on duration, but duration was most important for MSW.20 By contrast, in a US-based online study of over 500 MSM's preferences for prevention, an overall preference for male condoms vs. other PrEP delivery platforms was reported, and within PrEP delivery options, preferences were split between tablets and a nonvisible implant, with injections less frequently selected.9

There are several potential limitations to this study. These data come from a DCE, and DCE's measure hypothetical preferences for product attributes and levels, rather than acceptability rooted in actual experience. This methodology was necessary for this research because one LA injectable candidate was currently only available in phased trials, and no implant candidates were being tested among humans in Africa. A small systematic review provides some evidence that DCEs have fairly good ability (88%) to predict use of a product that is not currently used (opt-in).33 Second, the preferences and trade-offs included in this analysis are limited to those attributes and levels included in our DCE instrument and how these were understood and cognitively processed by our youth respondents. There may be other important components of LA PrEP that were not included. However, we completed formative research and cognitive interviews with our target population, to determine the most salient attributes and their levels. Finally, the DCE did not compare LA-PrEP formulations with oral PrEP, which may have enabled interesting or important preference comparisons or considerations.

In conclusion, this study demonstrates that male youth in South Africa, both MSW and MSM, are interested in LA-PrEP, with preferences defined by 3 classes of end users: those driven by dosing duration, those with comprehensive perspectives, and the smallest class driven by an injectable product form. The feasibility of delivery of injectable PrEP to male youth in a South African setting is currently unknown and may pose several complex implementation and policy challenges, nevertheless, end users are interested, and likely to uptake this technology recently reported to be highly efficacious.38 The interest in LA-PrEP, and the preferences expressed among these male South African youth, highlights potential demand and market segments that can and should be actively engaged as part of the movement to expand HIV prevention method options.45

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Keywords:

injection; implant; men; South Africa; LCA; long-acting PrEP

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