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Higher ART TDF/FTC Potency Correlates with Increased Protection against Rectal SHIV Transmission
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Reported by Jules Levin
CROI, Feb 2007, Los Angeles
J Garcia-Lerma1, R Otten1, S Qari1, M E Cong1, C Kim1, M Monsour1, R Schinazi2, R Janssen1, T Folks1, and Walid Heneine*1
1CDC, Atlanta, GA, US and 2VAMC, Decatur, GA, US
Chemoprophylaxis with antiretroviral drugs as a strategy to prevent the transmission of HIV is being explored, although information on the most effective drug modality is not yet known. Available data on tenofovir-DF (TDF) suggest that TDF at concentrations equivalent to those used in humans provides some protection in macaque models. Here, we assessed the ability of FTC alone or in combination with two different doses of tenofovir to protect macaques against rectal SHIV transmission, and the rationale for a higher antiretroviral potency is as important for PreP as for treatment.
HIV transmits sexually to a new host by first infecting a small number of founder cell populations at the mucosal point of entry. PreP exploits virus vulnerability at this early stage by blocking a low HIV burden from establishing itself and expanding towards a self-propagating infection.
To 6 rhesus macaques, divided into 3 groups, 3 drug treatments with different potencies were each given once daily. Group 1 was treated subcutaneously with a human equivalent dose of FTC (20 mg/kg). Group 2 received oral FTC/TDF (20 mg/kg FTC and 22 mg/kg TDF) at a dose equivalent to Truvada in humans. Group 3 received subcutaneous FTC (20 mg/kg) and a subcutaneous dose of TDF (22 mg/kg PMPA) that provides higher plasma TDF levels than the oral TDF dose in group 2. The 18 control macaques did not receive any drug treatment. Animals were exposed rectally once weekly for up to 14 weeks with a low dose of simian/human immunodeficiency virus (SHIV)SF162p3 (10 TCID50 or 7.5x106 vRNA) that expresses an R5 tropic HIV-1 envelope that resembles transmitted HIV-1. Exposures were stopped when a macaque became infected. Infection was monitored by serology and polymerase chain reaction (PCR) amplification of SHIV gag and pol sequences from plasma and peripheral blood lymphocytes, respectively.
RESULTS
Of the 18 control animals, 17 became infected after a median of 2 challenges (range 1 to 12). In group 1 macaques (subcutaneous FTC only), 4 of the 6 animals become infected after at exposures 5, 10, 12, and 13 (exact log-rank p = 0.004, Cox proportional hazard ratio [HR] = 3.8 compared to controls). Animals receiving FTC were at a 74% lower risk of SHIV infection than untreated animals during the study period (Hazard ratio=3.8, p=0.02). Infection of these 4 animals was delayed compared to controls (p=0.004). (In group 2 macaques (oral FTC/TDF), only 2 of the 6 animals become infected after 9 and 12 exposures (p = 0.0004, HR = 7.8). Animals receiving FTC/TDF were at 87% lower risk of SHIV infection during study period than untreated animals (Hazrad ratio = 7.8, p=0.008). All 6 group 3 macaques (subcutaneous FTC /PMPA) were fully protected after 14 challenges (p = 0.00005).
Despite the low viral burden at the early stages of mucosal infection, daily PreP with single drugs was only partially protective. Data demonstrate that full protection is possible and show a correlation between the level of protection and antiretroviral potency. The model suggests that chemoprophylaxis with potent drug combinations may be more effective than single drugs in preventing sexual HIV transmission in humans by increasing the antiviral activity of the regimen Data will help inform clinic trial design in humans.
Blunted Viremia in Macaques Failing Chemoprophylaxis with FTC or FTC/TDF Combination
J. Gerardo Garcia-Lerma*, R Otten, S Masciotra, S Qari, M E Cong, D Adams, J Johnson, R Janssen, T Folks, and W Heneine
CDC, Atlanta, GA, US
Chemoprophylaxis with ART like emtricitabine (FTC) and tenofovir (TDF) as a strategy to prevent HIV transmission is being explored. However, the emergence drug resistance, and viral and immunologic dynamics in persons who become infected while on prophylaxis are currently not defined. Macaques failing ART prophylaxis provide suitable models to assess such parameters. Here, we describe findings in rhesus macaques that became infected with simian-human immunodeficiency virus (SHIV) during chemoprophylaxis with FTC or a combination of FTC with TDF.
They studied 6 rhesus macaques infected rectally with SHIVSF162p3 during chemoprophylaxis with FTC (n = 4) or FTC/TDF (n = 2). Animals received daily subcutaneous injections with FTC (20 mg/kg) or an oral combination of FTC/TDF at doses equivalent to those used in humans (20 mg/kg FTC and 22 mg/kg TDF). ART was continued for 30 weeks after infection. Virus load dynamics and immunologic responses were monitored in these macaques and were compared with those seen in 13 untreated controls. Drug resistance was monitored by sequencing of SIV RT and by a sensitive real-time polymerase chain reaction (RT-PCR) assay for M184V.
Median peak viremia in treated macaques was 2.0 log10 lower than in untreated controls (4.9 ± 0.5 log10 vs 6.9 ± 0.3 log10) and remained low during a follow-up period of 9 to 28 weeks. All untreated controls had detectable viremia during a median follow-up of 7 weeks (range 5 to 36 weeks). In contrast, 2 FTC and 1 FTC/TDF failures had undetectable virus loads at weeks 3, 4, and 7, respectively. Breakthrough viruses were all wild type. The M184V mutation emerged in only 1 FTC and 1 FTC/TDF failure at 3 and 8 weeks after seroconversion, respectively. These 2 animals had higher peak viremias (7.13 log10 and 5.6 log10 vRNA/mL, respectively) than the 4 macaques that did not select M184V (5.4, 4.7, 4.3, and 3.5 log10 vRNA/mL) during extended treatment (median, 23 weeks). The TDF-associated K65R mutation was not detected in the 2 FTC/TDF failures.
Breakthrough infections with SHIV during chemoprophylaxis with FTC or FTC/TDF are associated with wild type viruses and a substantial reduction in viremia. Emergence of drug resistance correlated with higher plasma viremia and was not observed in animals that had substantially blunted viremias. Reduced primary viremias during chemoprophylaxis failure may have important implications regarding diminished transmissibility and slower disease progression.
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