TDF/FTC PrEP isn't cheap. Pharmacychecker.com lists monthly tabs ranging from $580 to $3180 for brand-name Truvada. Even if PrEPpers take TDF/FTC only 4 days a week, for example, at a cost of $20 per pill that adds up to $4160 a year, and at list price the cost would be much higher. If a person doesn't have insurance that will pay the bill, Douglas Krakower and Kenneth Mayer write, "out-of-pocket expenses are likely to be prohibitive for many high-risk persons."34 Gilead Sciences set up a PrEP Medication Assistance Program for "eligible HIV-negative adults in the United States who do not have insurance," their Website says. People can find out if they qualify by calling 1-855-330-5479 Monday through Friday between 9:00 AM and 8:00 PM Eastern time.
Los Angeles clinical investigators Theodoros Kelesidis and Raphael Landovitz estimate that "the cost of providing [TDF/FTC] PrEP to the 100,000 most at-risk people in the US could exceed $1 billion each year at current retail prices, which would exceed the CDC's current HIV prevention budget just with this intervention alone."45 Three studies tried to reckon the preventive power and cost-effectiveness of TDF/FTC PrEP among gay and bisexual men in the United States.
A 2008 modeling study of PrEP in US MSM figured the cost of once-daily TDF/FTC -- plus monitoring and care -- at $11,740 per person annually, and drug costs made up 91% of that tally.46 This model devised by Imperial College London investigators aimed to figure HIV cases prevented and cost-effectiveness of daily TDF/FTC PrEP among MSM in New York City over the course of 5 years. They figured costs based on the average wholesale cost of coformulated TDF/FTC in 2007. The model weighed different combinations of protection mechanism, efficacy, adherence, and population coverage. The researchers also modeled the impact of the three R's -- risk compensation, resistance, and renal impairment.
A PrEP program targeting 25% of high-risk New York City MSM would prevent 4% to 23% of the 19,510 infections predicted in the 5-year window.46 More than half of averted infections would involve men not taking PrEP but protected because of lowered HIV prevalence in the community. Across the range of input assumptions, TDF/FTC PrEP proved costeffective 75% of the time at a threshold of $50,000 per quality-adjusted life year (QALY) gained and 87.5% of the time at a threshold of $100,000 per QALY gained.
In 2009 researchers from Yale School of Medicine and other institutions calculated cost-effectiveness in MSM across the United States, with a base-case assumption of 50% TDF/FTC efficacy and a monthly cost of $753.47 This model also factored in the potential impact of differences in efficacy and risks of resistance, toxicity, and behavioral disinhibition.
In an MSM population averaging 34 years in age, daily PrEP would cut lifetime HIV infection risk from 44% to 25% and boost life expectancy modestly from 39.9 to 40.7 years.47 But at a steep cost of $298,000 per QALY saved, TDF/FTC PrEP would not be cost-effective in the base-case model. Cost per QALY saved dropped substantially to $107,000 if PrEP efficacy rose from 50% to 90% (about the rate among men with detectable drug levels in iPrEx), to $114,000 if drug costs got halved, and to $189,000 if the target population age fell to an average 20 years. But in an "extreme toxicity scenario," cost per QALY saved soared to $1.5 million. These investigators concluded that "with improvements in efficacy, targeting, or pricing, [TDF/FTC PrEP] may ... be cost-effective by current US standards."
In 2012 Stanford University researchers modeled the infection risk and cost-effectiveness of TDF/FTC PrEP in the general population of US MSM 13 to 64 years old and in certain MSM subgroups.48 The basecase scenario set TDF/FTC PrEP efficacy at 44% -- the overall iPrEx result. Dispensing PrEP to 20% of US MSM would trim the new-infection rate by 13% and add 550,166 QALYs over 20 years at $172,091 per QALY gained. For high-risk MSM with an average of 5 partners per year, PrEP would cost only $50,000 per QALY gained, but prescribing PrEP to all high-risk US MSM for 20 years would balloon healthcare costs $75 billion over current outlays. If the daily cost of TDF/FTC dropped to $15 or PrEP efficacy lay above 75% (as it did in adherent iPrEx men), PrEP for the general US MSM population would cost less than $100,000 per QALY gained. One might formulate the following bottom line from all three studies: PrEP could prevent many HIV infections in US gay and bisexual men over the next decade or so, but it costs a lot and may not be cost-effective at current TDF/FTC prices and if PrEP has only moderate efficacy. But lower costs and higher efficacy -- including levels achieved by adherent men in iPrEx -- could make PrEP costeffective by current standards.
And who will pay for PrEP? Insurance companies will pay, iPrEx investigator Robert Grant affirmed in an interview in this issue. "The payers in the United States have decided not to require HIV testing results before paying for antiretroviral medications," he noted, "and they do realize this means they are paying for PrEP." Of course many people with the highest risk of HIV infection do not have insurance.
Years from now, healthcare providers and others in the know will look at TDF/FTC PrEP the way they look at zidovudine today -- as an esteemed bellwether that may retain some niche function. Drug developers and clinical investigators are already well along in refining and testing new PrEP agents they hope will be more protective, safer, and easier to take than a once-a-day TDF/FTC pill.
So far future PrEP hopefuls fall into three (sometimes overlapping) groups -- current or investigational antiretrovirals with mechanisms different from TDF and FTC, longer-acting antiretrovirals that may be taken by mouth or injection, and longer-acting antiretrovirals suffused into vaginal rings (Figure 4).
|Figure 4. Three Options for Future PREP Agents|
Researchers are hard at work devising and testing PrEP agents that could improve on the activity, durability, and tolerability of TDF/FTC. (Pill and needle/syringe photos from Wikimedia Commons. Intravaginal ring photo from International Partnership for Microbicides.
Falling into the first category, the CCR5 antagonist maraviroc thwarts HIV infection at an earlier step in the viral replication cycle than reverse transcriptase inhibitors like TDF and FTC. NEXT-PrEP (HPTN 069) is a US double-blind placebo-controlled trial aiming to enroll 400 MSM and 200 heterosexual women to compare the 48-week safety and tolerability of daily maraviroc, maraviroc/FTC, maraviroc/TDF, and TDF/FTC.49
Nonnucleoside reverse transcriptase inhibitors are well known for their long half-lives, a property Janssen hopes to exploit in long-acting formulations of rilpivirine (TMC278LA) and dapivirine (TMC120). A study of a single intramuscular TMC278LA injection recorded high concentrations in plasma, genital tract fluid, and vaginal tissue of 27 HIV-negative women studied in London.50,51
A single 600-mg intramuscular injection of rilpivirine suspended in nanoparticles remained in circulation for 84 days in 10 HIV-negative women and 6 HIV-negative men tested by the same investigators.52 Vaginal tissue concentrations of rilpivirine were slightly lower than cervicovaginal fluid levels, but concentrations in male rectal tissue were higher than in rectal fluid. A phase 1/2 study of TMC278LA for PrEP ended early because of "additional safety information."53
Long-acting dapivirine is being studied both as a directly applied vaginal gel and in a vaginal ring, either alone54 or with maraviroc.55 Ideally, such rings could be inserted once a month, as contraceptive vaginal rings are today. In a double-blind placebocontrolled trial of a monthly dapivirine vaginal ring, 280 healthy, HIV-negative, sexually active women tolerated the ring well, and no serious safety concerns related to the ring arose.56 Two parallel phase 3 placebo-controlled trials of dapivirine are testing a once-monthly dapivirine ring in more than 5000 African women.57
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