DEL «DUALISMO NO CONCILIADO» AL DUALISMO DE LA CONCILIACIÓN

Although sexual lubricants are not intended to prevent HIV infection their use does provide a rationale for the development of similar microbicides that do have the potential to prevent HIV infection. As discussed below, lubricant use is a common practice among men and women and products have been used with vaginal and anal intercourse. However, some lubricants have the potential to cause mucosal disruption and potentially increased vulnerability to HIV infection. Lessons learned from the assessment of lubricant safety and acceptability can help focus the development of safe, acceptable, and effective rectal microbicides.

1.5.3.1 Sexual lubricant use by women

Sexual lubricant use is a relatively common practice among women in the developed world. Products are used for a variety of reasons including managing vaginal dryness or dyspareunia or for enhancement of sexual pleasure (Sutton, Boyer, Goldfinger, Ezer, & Pukall, 2012; Herbenick et al., 2011). Herbenick et al. conducted a survey of 2,056 US women of whom 62% had ever used a sexual lubricant and 25.3% had used a lubricant within

51 the last month (Herbenick et al., 2010). Data on lubricant used by women in the developing world are more complex. There are strong cultural norms about the desirability of vaginal dryness or lubrication. Braunstein and Van de Wijgert undertook a literature review and key informant interview process that suggested that women from countries such as India, Kenya, South Africa, Thailand and Zimbabwe are concerned about excess lubrication whereas women from Brazil and the US were more concerned about vaginal dryness (Braunstein & van de Wijgert, 2005). In a recent study where women were provided with a range of sexual lubricants and asked to complete an internet based survey it was apparent that the products were used for both vaginal and anal sex (Herbenick et al., 2011). In a more detailed study, Exner et al. conducted in-depth interviews with 28 women who had a history of RAI. Key findings included (i) condom use for anal sex was rare; 23 of the 28 women reported no condom use during the last episode of RAI and (ii) slightly less than half the women used a sexual lubricant; the reminder used saliva and/or vaginal fluid to facilitate RAI (Exner et al., 2008). These findings support the concept of developing dual compartment microbicides.

1.5.3.2 Sexual lubricant use by MSM

Carballo-Dieguéz et al. conducted a survey of rectal lubricant use among 307 Latino MSM in New York during 1995/1996. The majority of study participants (94%) had experience of using lubricants with RAI and 74% used a lubricant during at least 80% of all episodes of RAI. The study also demonstrated high rates of URAI (43%) with a willingness to use rectal microbicides if available (92%) (Carballo-Dieguez et al., 2000). A second

52 larger study conducted among 879 MSM living in San Francisco in 2002/2003 demonstrated high levels of URAI (36%), high levels of lubricant use (89%), including significant use of N9 containing products (26%) (Carballo-Dieguez et al., 2007). The study documented variability in microbicide acceptability based on the perceived level of protection afforded by microbicides. Whereas 65% of men would consider using a rectal microbicide if it was as effective as a condom, only 15% would consider using a microbicide if it was less effective than a condom. More recently, Clark et al. conducted a quantitative behavioral survey among 547 MSM from Lima, Peru (Clark et al., 2013). Approximately 50% of the men reported lubricant use with RAI; reasons for non-use included: no lubricant available (32%), used pre-lubricated condoms (24%), used saliva as a lubricant (13%), or could not afford to buy lubricant (8%). URAI was common among men using lubricants (63%). In a second recent study from Latin America, Kinsler et al. used Conjoint Analysis (CJA) to explore consumer preferences for potential rectal microbicides among 128 MSM in Peru, Ecuador, and Brazil (Kinsler et al., 2012). Parameters used in the CJA included: cost ($0.30 vs. $5.00), effectiveness (40% vs. 80%), side effects (none vs. some), dosing (before sex vs. daily), formulation (gel vs. liquid), dosage (15 vs. 35 mL), and availability (prescription vs. over the counter (OTC)). The favored product profile was a microbicide that was; $0.30, 80% effective, no side effects, use before sex, gel formulation, 15 mL dosage, and provided through a prescription. Although CJA does not involve consumers trying products it does provide an important framework for an ideal product. In this analysis, effectiveness had the greatest impact on product acceptability;

53 participants chose 80% rather than 40% (the level of protection seen in the CAPRISA 004 study (Abdool et al., 2010)) and price was also significant - $0.30 representing the approximate cost of a condom in Peru, Ecuador, or Lima.

1.5.3.3 Sexual lubricants and their potential for mucosal damage

In 2007, sexual lubricant sales in the US totaled more than $110 million (Andelloux, 2011). Currently within the US, lubricants are regulated as medical devices and therefore do not require the extensive preclinical and clinical testing required for drugs. Although there are a very large number of lubricants marketed in the US they can be broken down into a number of categories (Table 1.1).

54 Table 1-1 Categories of sexual lubricants

Category Examples Comments

Petroleum-based Petroleum jelly (Vaseline®)

Mineral oil Massage oil

Compatible with

polyurethane but not latex condoms

Natural oil Vegetable oil

Olive oil Coconut oil Crisco®

Compatible with

polyurethane but not latex condoms Water-based Astroglide® KY jelly® Wet® Liquid silk® Slippery stuff®

Most commonly used lubricants

Silicone-based Eros® Wet Platinum® Gun oil®

Hypoallergenic and condom compatible. Provides lubrication for longer than water-based lubricants

Several studies have been conducted to evaluate lubricant safety. Sudol et al. evaluated a number of OTC lubricants including KY-Plus (containing N9) in a mouse model wherein the mice received the test formulation followed by challenge with HSV-2 (Sudol & Phillips, 2004). In addition, mice also underwent rectal lavage, following product exposure, to determine whether formulations had the potential to cause rectal sloughing of epithelial cells. Use of KY-Plus was associated with significant cellular toxicity, enhancement of rectal HSV-2 infection, and rectal sloughing. Other, non- surfactant products such as Astroglide also increased HSV-2 infection and

55 rectal sloughing. Astroglide is known to be a hypersomolar gel (8,064 mOsm/kg; (Begay et al., 2011)) and in a subsequent study conducted in healthy volunteers, the use of hyperosmolar gels, including Astroglide, was associated with significant mucosal injury (Fuchs et al., 2007). Begay et al. evaluated a total of 41 lubricants for their osmolality, potential cytotoxicity (using an XTT assay), and antiviral activity against HIV (using TZM-bl cell lines and CXCR4 and CCR5 tropic HIV) (Begay et al., 2011). Product osmolality varied from 15 (FemGlide™) to 9,177 (ForPlay® Gel Plus) mOsm/Kg. None of the products inhibited HIV infection but four products (all Astroglide derivatives with high osmolality) significantly enhanced HIV replication. Dezzutti et al. recently published data on OTC lubricant safety using ectocervical and colorectal explant tissues (Dezzutti et al., 2012). All of the hyperosmolar gels were associated with cellular toxicity and epithelial damage and did not appear to have any antiviral activity (Table 1.2).The two iso-osmolar products (Good Clean Love and PRÉ) as well as the two silicone-based products (Female Condom 2 lubricant and Wet Platinum) were found to be safe in the testing algorithm.

56 Table 1-2 Physical characteristics of OTC lubricants

Lubricant Osmolality (mOsm/kg) pH CC50 ED50 Therapeutic Index Aqueous-based  Astroglide 6,113 4.0 0.9 0.8 1  Elbow Grease 3,865 5.7 5.7 0.4 14

 Good Clean Love 269 4.8 >1,000 0.6 >1,000

 Gynol II 1,406 4.7 0.4 0.1 4  ID Glide Ultra 3,150 5.2 4.8 0.8 6  KY Jelly 2,510 4.5 11.8 5 2  PRÉ 502 7.3 308 4.4 70  Replens 1,875 2.9 19.8 0.5 40  Slippery stuff 26 6.8 > 1,000 26 >40  Sliquid Organic 106 6.8 3.0 3.9 0.8 Lipid-based

 Boy Butter H2O 1,307 7.4 ND ND ND

 Boy Butter original NA NA ND ND ND

Silicone based

 FC 2 lubricant NA NA ND ND ND

 Wet Platinum NA NA ND ND ND

Adapted from Dezzutti et al. (Dezzutti et al., 2012); ND: Not determined; NA: Not applicable

An important, but as yet unanswered, question is whether the use of currently available lubricants could be harmful and/or increase the risk of HIV infection associated with URAI. It is known that the frequent use of an N9-based vaginal microbicide was associated with an increase in HIV acquisition in the COL1492 study (Van et al., 2002) but, with the exception of some spermicidal products, N9 is no longer used in sexual lubricants.

57 However, Gorbach et al. have suggested that consistent rectal use of lubricants (defined as use of a lubricant in the prior month) was associated with an increased risk of STIs including rectal gonorrhoea (GC)/chlamydia (CT) infection. The cross-sectional study was conducted in a very heterogeneous population including HIV-positive and negative men and women. Lubricant use was based on participant recall. A definitive, if challenging, study to answer the question as to whether lubricants could increase STI acquisition including HIV would require enrollment of an at risk population into a large prospective study. In the absence of definitive data, but based on the preclinical studies from Begay and Dezzutti (Begay et al., 2011; Dezzutti et al., 2012), it seems appropriate to counsel individuals to use iso-osmolar water soluble lubricants whenever possible.