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Efficacy of topical tenofovir against transmission of a tenofovir-resistant SHIV in macaques.

Dobard CW, Sharma S, Cong ME, West R, Makarova N, Holder A, Pau CP, Hanson DL, Novembre FJ, Garcia-Lerma JG, Heneine W - Retrovirology (2015)

Bottom Line: SHIV162P3K65R shows approximately a 5-fold reduction in susceptibility to TFV compared to wild-type SHIV.The findings in this model do not predict complete loss of protection by topical TFV against vaginal exposure to HIV-1K65R viruses and provide a tissue drug target for high efficacy.These data will facilitate the development of TFV delivery platforms that have high activity on both wild-type and TFV-resistant viruses.

View Article: PubMed Central - PubMed

Affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, MS G45, 1600 Clifton Road, Atlanta, GA, 30329, USA. cdobard@cdc.gov.

ABSTRACT

Background: Topically delivered tenofovir (TFV) from intravaginal rings, tablets, or gels is being evaluated for HIV prevention. We previously demonstrated that TFV delivered vaginally by gel protected macaques from vaginal infection with SHIV. Here we investigated efficacy of the TFV gel against vaginal transmission of a TFV-resistant SHIV containing the K65R mutation (SHIV162P3K65R) and its relationship to drug levels in vaginal tissues.

Results: SHIV162P3K65R shows approximately a 5-fold reduction in susceptibility to TFV compared to wild-type SHIV. Efficacy was evaluated in pig-tailed macaques exposed vaginally twice-weekly (up to 10 weeks) to SHIV162P3K65R 30 min after receiving placebo (n = 6) or 1% TFV (n = 6) gel. Four of the six controls were infected after a median of 5 exposures. In contrast, five of six macaques that received TFV gel remained uninfected after 20 vaginal SHIV162P3K65R exposures, resulting in an estimated efficacy of 75%. The mean intracellular TFV-diphosphate (TFV-DP) concentrations in vaginal lymphocytes 4 h after a single gel dose were found to be high (1,631 fmol/10(6) cells, range 492-3,847) and within the in vitro IC75 range (1,206 fmol/10(6) cells) for SHIV162P3K65R.

Conclusion: Both the modest resistance conferred by K65R and the high TFV-DP exposure in vaginal lymphocytes, likely explain the observed protection. The findings in this model do not predict complete loss of protection by topical TFV against vaginal exposure to HIV-1K65R viruses and provide a tissue drug target for high efficacy. These data will facilitate the development of TFV delivery platforms that have high activity on both wild-type and TFV-resistant viruses.

No MeSH data available.


Related in: MedlinePlus

Efficacy of TFV gel against SHIV162P3K65R. a Survival curves representing the cumulative percentage of uninfected macaques as a function of the number of challenges. After 20 SHIV162P3K65R exposures, challenges were stopped and animals were monitored for ten additional weeks for infection in the follow-up period. b Breakthrough infections show no evidence of blunted viremia. Individual virus load kinetics of controls (black lines) and breakthrough infection (red line) under continued twice-weekly gel dosing. Time zero indicates the time of first SHIV RNA detection in plasma. Time zero indicates the time of first SHIV RNA detection in plasma. The dashed line denotes the limit of quantification of the virus load assay (50 copies/ml).
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Fig1: Efficacy of TFV gel against SHIV162P3K65R. a Survival curves representing the cumulative percentage of uninfected macaques as a function of the number of challenges. After 20 SHIV162P3K65R exposures, challenges were stopped and animals were monitored for ten additional weeks for infection in the follow-up period. b Breakthrough infections show no evidence of blunted viremia. Individual virus load kinetics of controls (black lines) and breakthrough infection (red line) under continued twice-weekly gel dosing. Time zero indicates the time of first SHIV RNA detection in plasma. Time zero indicates the time of first SHIV RNA detection in plasma. The dashed line denotes the limit of quantification of the virus load assay (50 copies/ml).

Mentions: Vaginal 1% TFV gel provided complete protection against wild-type SHIV162P3 when applied 30 min before virus challenge [9]. Figure 1 shows infection outcomes after a maximum of 20 challenges in macaques who received either placebo or 1% TFV gel 30 min before vaginal exposure to SHIV162P3K65R. Four of six macaques in the placebo group became infected after a median of 5 challenges (at exposure 3, 5, 5, and 17). In contrast, five of six macaques in the TFV group remained SHIV negative as measured by both PCR and serology throughout the challenge period and 10-week washout. The breakthrough infection in the TFV treatment group occurred at challenge 8. The efficacy of TFV gel was estimated at 75% based upon 4/6 infections in the control group compared to 1/6 in the TFV treated group. However, due to small group numbers and low transmissibility of SHIV162P3K65R (67% infection rate), the protective effect in animals treated with TFV gel and risk of infection between the two groups was not statistically significantly (p = 0.24, Fisher’s exact test).Fig. 1


Efficacy of topical tenofovir against transmission of a tenofovir-resistant SHIV in macaques.

Dobard CW, Sharma S, Cong ME, West R, Makarova N, Holder A, Pau CP, Hanson DL, Novembre FJ, Garcia-Lerma JG, Heneine W - Retrovirology (2015)

Efficacy of TFV gel against SHIV162P3K65R. a Survival curves representing the cumulative percentage of uninfected macaques as a function of the number of challenges. After 20 SHIV162P3K65R exposures, challenges were stopped and animals were monitored for ten additional weeks for infection in the follow-up period. b Breakthrough infections show no evidence of blunted viremia. Individual virus load kinetics of controls (black lines) and breakthrough infection (red line) under continued twice-weekly gel dosing. Time zero indicates the time of first SHIV RNA detection in plasma. Time zero indicates the time of first SHIV RNA detection in plasma. The dashed line denotes the limit of quantification of the virus load assay (50 copies/ml).
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4528693&req=5

Fig1: Efficacy of TFV gel against SHIV162P3K65R. a Survival curves representing the cumulative percentage of uninfected macaques as a function of the number of challenges. After 20 SHIV162P3K65R exposures, challenges were stopped and animals were monitored for ten additional weeks for infection in the follow-up period. b Breakthrough infections show no evidence of blunted viremia. Individual virus load kinetics of controls (black lines) and breakthrough infection (red line) under continued twice-weekly gel dosing. Time zero indicates the time of first SHIV RNA detection in plasma. Time zero indicates the time of first SHIV RNA detection in plasma. The dashed line denotes the limit of quantification of the virus load assay (50 copies/ml).
Mentions: Vaginal 1% TFV gel provided complete protection against wild-type SHIV162P3 when applied 30 min before virus challenge [9]. Figure 1 shows infection outcomes after a maximum of 20 challenges in macaques who received either placebo or 1% TFV gel 30 min before vaginal exposure to SHIV162P3K65R. Four of six macaques in the placebo group became infected after a median of 5 challenges (at exposure 3, 5, 5, and 17). In contrast, five of six macaques in the TFV group remained SHIV negative as measured by both PCR and serology throughout the challenge period and 10-week washout. The breakthrough infection in the TFV treatment group occurred at challenge 8. The efficacy of TFV gel was estimated at 75% based upon 4/6 infections in the control group compared to 1/6 in the TFV treated group. However, due to small group numbers and low transmissibility of SHIV162P3K65R (67% infection rate), the protective effect in animals treated with TFV gel and risk of infection between the two groups was not statistically significantly (p = 0.24, Fisher’s exact test).Fig. 1

Bottom Line: SHIV162P3K65R shows approximately a 5-fold reduction in susceptibility to TFV compared to wild-type SHIV.The findings in this model do not predict complete loss of protection by topical TFV against vaginal exposure to HIV-1K65R viruses and provide a tissue drug target for high efficacy.These data will facilitate the development of TFV delivery platforms that have high activity on both wild-type and TFV-resistant viruses.

View Article: PubMed Central - PubMed

Affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, MS G45, 1600 Clifton Road, Atlanta, GA, 30329, USA. cdobard@cdc.gov.

ABSTRACT

Background: Topically delivered tenofovir (TFV) from intravaginal rings, tablets, or gels is being evaluated for HIV prevention. We previously demonstrated that TFV delivered vaginally by gel protected macaques from vaginal infection with SHIV. Here we investigated efficacy of the TFV gel against vaginal transmission of a TFV-resistant SHIV containing the K65R mutation (SHIV162P3K65R) and its relationship to drug levels in vaginal tissues.

Results: SHIV162P3K65R shows approximately a 5-fold reduction in susceptibility to TFV compared to wild-type SHIV. Efficacy was evaluated in pig-tailed macaques exposed vaginally twice-weekly (up to 10 weeks) to SHIV162P3K65R 30 min after receiving placebo (n = 6) or 1% TFV (n = 6) gel. Four of the six controls were infected after a median of 5 exposures. In contrast, five of six macaques that received TFV gel remained uninfected after 20 vaginal SHIV162P3K65R exposures, resulting in an estimated efficacy of 75%. The mean intracellular TFV-diphosphate (TFV-DP) concentrations in vaginal lymphocytes 4 h after a single gel dose were found to be high (1,631 fmol/10(6) cells, range 492-3,847) and within the in vitro IC75 range (1,206 fmol/10(6) cells) for SHIV162P3K65R.

Conclusion: Both the modest resistance conferred by K65R and the high TFV-DP exposure in vaginal lymphocytes, likely explain the observed protection. The findings in this model do not predict complete loss of protection by topical TFV against vaginal exposure to HIV-1K65R viruses and provide a tissue drug target for high efficacy. These data will facilitate the development of TFV delivery platforms that have high activity on both wild-type and TFV-resistant viruses.

No MeSH data available.


Related in: MedlinePlus