| |
|
Safety and tolerability of vaginal PRO 2000 gel in sexually active HIV-uninfected and abstinent HIV-infected women
|
| |
| |
The HIV pandemic is spreading rapidly among women and men in the developing world. Consistent condom use requires cooperative partners and the development and distribution of a safe and effective HIV vaccine will take
many years so there is an urgent need for the development of efficacious, convenient and inexpensive microbicides.
Unfortunately, the most widely studied microbicide, nonoxynol-9 (N-9), has not been shown to be protective in several large phase III trials, despite in vitro activity against HIV. Moreover, concerns have been raised about nonoxynol-9 toxicity. These findings underscore the need to find novel topical microbicides with mechanisms of action that do not elicit an inflammatory response.
One such novel microbicidal agent currently under investigation is PRO 2000 (Interneuron Pharmaceuticals, Inc.), a synthetic naphthalene sulfonate polymer. PRO 2000 Gel is an aqueous gel formulation containing the synthetic polymer, a pH 4.5 buffer system and common preservatives.
Non-cytotoxic PRO 2000 concentrations of 0.01% (100 [mu]g/ml) or less have been shown to block HIV infection of T lymphocytes, macrophages and cervical explant tissue in vitro. Moreover, it has been shown to protect against
vaginal HIV transmission in non-human primate models. The compound binds to the HIV envelope glycoprotein (gp120) and interferes with one or more early events in the HIV-1 infection process, including CD4 binding and events mediated by the V3 loop region. PRO 2000 is also active in vitro against herpesviruses, Chlamydia trachomatis, and Neisseria gonorrhoeae, but not against Candida albicans or Lactobacillus spp. At concentrations up to 4% (and unpublished data). The vaginal gel was shown to protect against vaginal HSV-2
infection in a mouse model.
PRO 2000 has been studied in 73 low-risk, sexually abstinent European women, who were randomized to apply a placebo, 0.5% PRO 2000, or 4% PRO 2000 intravaginally once daily for 14 intermenstrual days [24]. There were no
serious adverse events, although increased vaginal discharge was commonly noted, and a minority of participants reported either transient vaginal bleeding or urogenital symptoms. There was no evidence of systemic toxicity or product
absorption.
Because of the promising in vitro and animal protection data, and the safety and tolerability of PRO 2000 Gel in abstinent participants, a protocol team within the HIV Prevention Trial Network [HPTN; funded by the National
Institutes of Health (NIH)] was established to assess the safety and tolerability of increasing concentrations and frequencies of PRO 2000 Gel in sexually active HIV-uninfected women and then to evaluate the highest tolerated dose
for safety in HIV-infected, sexually abstinent women.
AIDS 2003; 17(3):321-329
Kenneth H. Mayer a; Salim Abdool Karim b; Clifton Kelly c; Lisa Maslankowski d; Helen Rees e; Albert T. Profy f; Jennifer Day g; Julie Welch h; Zeda Rosenberg h; for the HIV Prevention Trials Network (HPTN) 020 Protocol Team *
STUDY
Objectives: To evaluate once or twice daily vaginal exposure to 2 and 4% PRO 2000 Gel, a naphthalene sulfonate polymer microbicide, in sexually active HIV-uninfected women to determine the highest tolerated frequency and concentration combination, and to assess this in sexually abstinent HIV-infected women.
Methods: Sixty three women from Providence, Philadelphia, Durban and Johannesburg were enrolled after being screened to exclude pre-existing illnesses and were instructed to use the product once or twice daily for 14 intermenstrual days. They underwent colposcopy prior to product use and after 14 days of product use, with a pelvic examination at day 7.
Results: The product was well tolerated, with no serious adverse events, even though 73% of the participants had at least one adverse experience: 82% of these were classified as mild, and over 90% of the findings and symptoms were localized to the genital tract. Women who used the 4% gel twice daily tended to have more adverse events than all the other groups. Three participants did not complete the study; one because of Herpes simplex virus cervicitis, the second because of epithelial disruption, and the third because she became be pregnant. The remaining participants adhered to the study protocol and indicated that they would use the product if it were shown to be effective.
Conclusions: PRO 2000 Gel was safe and well tolerated in sexually active HIV-uninfected and sexually abstinent HIV-infected women, enabling the product to be considered for evaluation in efficacy trials.
Discussion by authors
PRO 2000 Gel was safe and well tolerated when used once or twice daily at either 2 or 4% concentrations in low-risk sexually active, HIV-uninfected women and at 4% twice daily in abstinent HIV-infected women. In this phase I study,
there was no evidence of significant absorption or systemic toxicity. The most common adverse events were mild, transient genitourinary discomfort or bleeding, which did not result in product discontinuation. Increased vaginal
discharge was common, most often associated with leakage of study product, and was generally well tolerated by participants. Sexual intercourse tended to result in removal of excess product and diminution of discharge.
In European trials of PRO 2000 Gel, among the participants who used the placebo preparation, 8% reported intermenstrual spotting, 8% reported vulvovaginal pain or soreness, 8% reported vaginal pruritus, and 24% reported
vulvar pruritus over 2 weeks of exposure. Therefore, many of the symptoms reported in the current study may not have been a result of the active ingredient in the PRO 2000 Gel.
The results of the current study are similar to the earlier European studies of PRO 2000 in abstinent women, where participants applied placebo, 0.5% or 4% PRO 2000 Gel once daily between menses. Overall, the spectrum of clinical
events was similar across the studies. In a natural history study of 26 women who were monitored for changes in vaginal microflora and symptomatology, 73% reported irritation during the 8 weeks of observational study, which
was comparable to the level reported in this study, suggesting that not all of the symptoms reported by women were necessarily caused by the product.
In the current study and prior European trials, there was a trend towards increased adverse events at the highest concentration (4%) and frequency tested. In our study, significantly more symptoms and a trend towards increased clinical findings were reported by women who used the 4% gel twice daily. This phase I study was not sufficiently powered to make statistical comparisons between study arms, resulting in limited power to detect differences. Therefore, the findings that suggest more clinical events in participants with greater product exposure should be interpreted
carefully, in conjunction with other data. Higher product concentrations were also associated with more genital tract abnormalities in primate studies (D. Patton, University of Washington, personal communication). Although the 4%
concentration was tolerated by the vast majority of participants, the tendency towards more adverse experiences in a controlled environment with low-risk volunteers may suggest that the use of lower concentrations in future studies of high-risk populations is indicated. Substantially lower PRO 2000 concentrations have provided protection in animal models. In vitro concentrations of 0.01% or less have prevented HIV infection in cervical explant and other model systems. A large, multinational phase III study of PRO 2000 (HPTN 035) will evaluate the effectiveness of 0.5% PRO 2000 in preventing HIV transmission.
It is not fully evident the extent that PRO 2000 exposure contributed to epithelial disruption events detected in this study. Among the 15 participants who had disruptions, two had coexistent HSV genital tract infection, six had documented or suspected trauma associated with the applicator or speculum, and one each reported a shaving cut, problems with digitally removing a condom fragment, and physical trauma. Other trauma could have been under-reported, so that additional findings might be caused by factors that were unrelated to the study product. Applicator trauma was associated with epithelial disruption in four participants, including one episode of vaginal bleeding, and may have contributed to four additional findings of unknown cause. In some participants, lesions appeared to follow the rounded
outline of the applicator tip. The product insertion instructions emphasized the need to insert the applicator as far as possible, and this may have contributed to the problem. Further research in optimal vaginal microbicide delivery systems is warranted.
It is not clear to what extent the product itself contributed to the observed mucosal findings, since abnormalities often resolved or appeared to be improving in the presence of continued PRO 2000 Gel use. It is possible that the physical properties of the gel may have contributed to the observed lesions. Some participants noted that the product partially solidified and could feel sticky. Fewer adverse events were seen in sexually active women in this study as well as in a prior vaginal microbicide study using BufferGel. It is possible that the penis may act as a 'plunger' and decrease residual product in the vagina, mixing the gel and preventing hardening that could abrade the mucosa. Because of the multiplicity of factors that may result in cervicovaginal mucosal abnormalities and genital tract symptoms, it may be desirable that future early-phase microbicide studies include inactive placebo and non-interventional observational control groups.
Since topical microbicides will need to act in a complex microenvironment, we also assessed the effects of PRO 2000 Gel on vaginal pH and microflora. An acidic pH is associated with inactivation of HIV and other sexually
transmitted pathogens. After 2 weeks of exposure to PRO 2000 Gel, the mean vaginal pH remained the same, approximately 5.0, with none of the women developing an alkaline pH. One woman developed symptomatic bacterial
vaginosis, but none developed symptomatic vaginal candidiasis while using PRO 2000. The serial assessment of mean microflora scores indicated that the prevalence of lactobacilli decreased somewhat over 2 weeks of PRO 2000 Gel use, but variability was great between participants. The decreases in lactobacilli could be a result of microflora dilution by the gel, but lactobacilli concentrations should continue to be monitored in future PRO 2000 trials to improve understanding of the gel's antimicrobial activity. Although PRO 2000 was found to be active against HSV-2 in vitro and in animal models, three participants developed findings consistent with HSV-2 vulvitis, cervicitis and proctitis. It is not clear that the inability of the product to prevent reactivation is at variance with the protective effect against primary HSV infection in the murine model, so further assessment of PRO2000's in vivo activity against HSV-2 is needed.
In summary, 2 or 4% PRO 2000 Gel was well tolerated by sexually active HIV-uninfected women when used once or twice daily. Although some women reported transient and limited vaginal discomfort or bleeding, or product leakage, none of them discontinued product use. Pelvic examination and colposcopy also detected discrete epithelial disruptions in 24% of the study participants; however, in the majority, the product itself did not appear to play a clear role in disrupting the genital tract mucosa. Increased findings and symptoms noted among women who used the 4% concentration twice daily suggest the need to use lower concentrations and/or dosing frequencies in future trials. The product was also well tolerated by HIV-infected women. The results of this trial justify the evaluation of this product in large-scale efficacy trials to assess its possible role in limiting HIV transmission.
|
|
| |
| |
|
|
|
