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Preventing HIV transmission: prophylactic TDF/FTC and resistance to a vaginal microbicide
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Mark Mascolini
Resistance Workshop Review: Part 3
XV Intl HIV Drug Resistance Workshop
June 13-17, 2006, Sitges, Spain
Studies in Rhesus monkeys yielded some possibly good news-and some possibly bad news-about blocking sexual transmission of HIV. The good news is that tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) may stonewall HIV better than one drug alone; the bad news is that HIV may become resistant to a candidate vaginal microbicide after a single dose.
Two nukes better than one in blocking HIV
Two reverse transcriptase inhibitors prevented rectal transmission of simian/human immunodeficiency virus (SHIV) in all six monkeys pretreated with TDF and FTC, whereas FTC alone protected only 2 of 6 pretreated monkeys [1]. Walid Heniene from the US Centers for Disease Control (CDC) cautioned that the results do not necessarily mean the same regimen will consistently block sexually transmitted HIV in humans because he used a higher TDF dose than humans take in fixed-dose TDF/FTC (Truvada).
Heniene injected 6 Rhesus macaques with TDF/FTC (22/20 mg/kg once daily), while another 6 got FTC alone (20 mg/kg once daily) or no treatment for 9 days before rectal exposure to low doses of SHIVSF162p3, a simian virus shrouded in an HIV-1 envelope bearing CCR5 coreceptors-an envelope just like the HIV-1 transmitted sexually between humans. The macaques got challenged with this virus once a week for 14 weeks.
At that point the CDC team stopped giving the monkeys antiretrovirals, and 14 weeks later they searched for SHIV in the animals' blood with a polymerase chain reaction (PCR) assay.
Of the 6 untreated monkeys and 7 other macaques exposed earlier to SHIV in other studies, 14 (93%) became infected after a median of 2 SHIV challenges (range 1 to 10). Four of 6 macaques pretreated only with FTC contracted SHIV infection after 5, 10, 12, and 13 challenges (P = 0.005 versus controls). A multivariate statistical analysis figured that FTC-treated animals were 3.9 times less likely to become infected than were untreated controls (P = 0.021). All 6 macaques injected with TDF/FTC fended off all 14 SHIV challenges (P = 0.00013 versus untreated controls).
In earlier studies TDF by itself shielded macaques from SHIV, but consistent protection required a higher dose than humans use. Heniene believes his results indicate that double therapy can fight off sexually transmitted HIV better than one-drug prophylaxis, but the monkey results must be verified at TDF doses equivalent to those people use.
Resistance to a vaginal microbicide
Fervid research will probably devise vaginal microbicides that protect women from HIV long before an HIV vaccine jumps phase 3 trial hurdles (if one ever does). And an anti-HIV microbicide would at last put protection in the hands of women, who account for an ever-growing proportion of HIV infections worldwide. But work by Dawn Moore at Cleveland's Case Western Reserve University suggests that resistance can threaten microbicides as surely as it threatens antiretroviral therapy [2].
Moore's findings seem especially disappointing because no one had yet demonstrated resistance against the microbicide candidate she tested, PSC-RANTES. Serial passage studies-the classic method for prodding antiretroviral resistance mutations to evolve-had turned up mutations rendering HIV-1 resistant to other entry inhibitors but not to PSC-RANTES, a derivative of the natural human chemokine RANTES, which binds to CCR5 coreceptors on T cells. Researchers surmised that PSC-RANTES defied resistance because-besides barring viral docking to CCR5-it appears to make cells suck this critical receptor back inside their walls. But Moore's results indicate that HIV-1 can become resistant to PSC-RANTES anyway.
At high concentrations, Moore found, PSC-RANTES kept a simian/human immunodeficiency virus (SHIV) from infecting monkeys exposed to that virus. But as she sequentially lowered the PSC-RANTES concentration, more macaques became infected. Moore uncovered two mutations in the viral envelope gene that emerged in one animal treated with a single dose of 100 mM of PSC-RANTES-which she characterized as a "moderate to high" dose of the entry inhibitor.
An assays that scouts out viral species making up only 0.4% of a viral population confirmed low frequencies of a K315R substitution in the envelope protein gp120 and an N640D substitution in the envelope protein gp41 in virus from this infected macaque. Moore noted that the rapid emergence of resistant virus in this monkey "forecasts possible difficulties in anti-HIV-1 microbicide treatment."
Mark Mascolini writes about HIV infection
References
1. Garcia-Lerma JG, Otten R, Qari S, et al. Prevention of rectal SHIV transmission in macaques by tenofovir/FTC combination. Antivir Ther 2006;11:S107.
2. Moore DM, McGhee JL, Veazey RS, Arts EJ. Selection of drug resistance mutations in SHIVSF162 following a single dose treatment of the microbicide PSC-RANTES in a rhesus macaque model. Antivir Ther 2006;11:S147.
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