druginfo-boun...@lists.hst.org.za] On Behalf Of Andy Gray
Sent: 29 June 2012 11:03 AM
To: drugi...@lists.hst.org.za
Subject: [druginfo] Lancet: Pre-exposure prophylaxis for HIV prevention:
how to predict success

Hi all

This Lancet commentary relates to the posting yesterday about the role of
ITT analyses. It proposes some stringent pre-clinical requirements for any
future PrEP studies.

regards
Andy
~~~

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)618...
The Lancet, Volume 379, Issue 9835, Pages 2409 - 2411, 30 June 2012
doi:10.1016/S0140-6736(11)61852-7
Published Online: 07 December 2011

Pre-exposure prophylaxis for HIV prevention: how to predict success

Angela DM Kashuba a, Kristine B Patterson b, Julie B Dumond a, Myron S
Cohen b

Use of antiretroviral drugs to prevent sexual transmission of HIV-1 has
been a critical priority since their development. In the past 2 years
results from seven important prevention trials have been reported (table).
One of the trials, HPTN 052,1 showed nearly complete prevention of HIV
transmission when viraemia was suppressed. The other studies focused on
antiretroviral agents for pre-exposure prophylaxis: two used 1% tenofovir
gel (CAPRISA 0042 and VOICE3), four used oral tenofovir disoproxil fumarate
(TDF) and emtricitabine (FTC) in combination
(iPrEX,4 TDF2,5 Partners in Prevention [PIP],6 and Fem-PrEP7), and two used
oral TDF alone (VOICE3 and PIP6). Somewhat confusingly, the findings of
these studies have led to reports both of successful prevention of HIV
infection (CAPRISA 004,2 iPrEx,4 TDF2,5 and PIP6) and of futility (VOICE3
and Fem-PrEP7).

<snip - Table: Antiretroviral-based HIV prevention studies>

Clearly, results on pre-exposure prophylaxis will be used to inform policy
and to plan future research, and so the trials' findings need to be
considered carefully. There were key differences in the pre-exposure
prophylaxis trials (table): each included different populations with
distinct routes of HIV transmission. For example, iPrEx4 was the first
success for oral pre-exposure prophylaxis and focused on men who have sex
with men. It is reasonable to assume that anal intercourse was the key
route of transmission in the iPrEx trial,4 and was less frequently the
source of HIV infection in the heterosexual women and men in the
Fem-PrEP,7 VOICE,3 TDF2,5 and PIP6 studies. HIV acquisition is more
efficient after anal intercourse,8 and more HIV variants are acquired
during anal intercourse than cervicovaginal exposure.9

We have reported substantial differences in antiretroviral drug
concentrations in mucosal tissues.10—12 After oral administration of
co-formulated TDF and FTC, there were 100-fold higher concentrations of
tenofovir in rectal tissue compared with cervicovaginal tissue.12
Intracellularly phosphorylated tenofovir (TFV-DP) and emtricitabine
(FTC-TP) are required to inhibit HIV replication.12 100-fold higher
concentrations of TFV-DP were detected in the rectum as compared with
cervix and vagina.12 Conversely, FTC-TP concentrations were 10—15 fold
higher in vaginal and cervical tissue than in rectal tissue. Although we do
not know the concentrations of TFV-DP and FTC-TP required to prevent HIV
infection, the differences in tissue concentrations are substantial and
suggest implications for HIV prevention. In the VOICE trial,3 the lack of
protection with oral TDF could reflect low tissue concentrations of the
drug. How, then, can we explain the protection provided by TDF in PIP6? It
seems possible that HIV transmission in a discordant couple relationship
might be prevented differently, or more readily. It is also possible,
indeed likely, that adherence in a discordant relationship is better,
resulting in a critical (currently unknown) tissue concentration being
achieved. The protection from HIV observed with the TDF and FTC combination
in TDF25 and PIP6 suggests an important role for higher FTC concentrations,
perhaps in combination with the lower concentrations of tenofovir, in the
female genital tract. The differences in benefit of 1% tenofovir gel in
CAPRISA 0042 and VOICE3 demand further exploration; the studies used
different dosage schedules, and women at different sites might differ in
ways that affect study outcomes (table).

Adherence, however, will still determine the value of antiretroviral agents
both in clinical trials and in clinical practice. In HPTN 0521 HIV viraemia
was prospectively monitored in infected trial participants to ensure
adherence, which allowed determination of the antiretrovirals'
ability to suppress transmission under ideal conditions. To date, the only
prospective measurement of adherence in pre-exposure prophylaxis trials has
been by self-report or pill counts, which might overestimate
adherence.13 These values have then been compared to potential efficacy
with post-hoc measurement of blood concentrations in a limited number of
samples using a case-control design. In the iPrEx trial,4 the investigators
used combined data to argue that pre-exposure prophylaxis was perhaps more
than 90% protective in participants who took the treatment reliably. In
CAPRISA 004,2 the effectiveness of protection was 52% with more than 80%
adherence as measured retrospectively by evaluation of used gel
applicators. But such retrospective analyses cannot be used to confirm the
intervention's success or failure. Less adherence to daily use of 1%
tenofovir gel in VOICE3 could have compromised benefit relative to the
coitally-driven use of the gel in CAPRISA 004.2 Paradoxically, daily use
may confer a degree of difficulty that reduces adherence.

We believe that, before future pre-exposure prophylaxis studies are
undertaken, knowledge of biological plausibility must be secure.
Evidence of strong and durable tissue concentrations of active agents
should be a condition of such studies taking place. Powerful antiviral
agents limited in their tissue penetration, intracellular metabolism, or
tissue half-life are not appropriate for pre-exposure prophylaxis.
Moreover, adherence must be measured prospectively in future trials.14,
15 Under these conditions trial participants who do not adhere to treatment
can be counselled or the study analysis designed to incorporate these most
rigorous measures of adherence. To predict success in clinical practice
reliably, both the drug concentrations needed for protective efficacy and
the best way to assess adherence in clinical trials must first be defined.
Effectiveness trials that depend on adherence and many other factors—the
real world—should await proof that antiretroviral agents work as
anticipated.

ADMK has received research grants from Abbott Laboratories,
GlaxoSmithKline, Jansen Pharmaceuticals, Merck, and Pfizer, and has
received honoraria from Merck and Bristol-Myers Squibb. KBP has received
research grants from Abbott Laboratories, GlaxoSmithKline, Jansen
Pharmaceuticals, Merck, and Pfizer, and has also served on a women's
advisory board and as a consultant for Jansen Pharmaceuticals. JBD and MSC
declare that they have no conflicts of interest.

References
1 Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with
early antiretroviral therapy. N Engl J Med 2011; 365: 493-505.
2 Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and
safety of tenofovir gel, an antiretroviral microbicide, for the prevention
of HIV infection in women. Science 2010; 329: 1168-1174.
3 VOICE (MTN-003) Microbicide Trials Network.
http://www.mtnstopshiv.org/news/studies/mtn003. (accessed Nov 28, 2011).
4 Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for
HIV prevention in men who have sex with men. N Engl J Med 2010; 363:
2587-2599.
5 Thigpen M, Kebaabetswe P, Smith D, et al. Daily oral antiretroviral use
for the prevention of HIV infection in heterosexually active young adults
in Botswana: results from the TDF2 study. 6th IAS Conference; July 17—20,
2011. Rome, Italy. WELBC01 oral abstract.
http://pag.ias2011.org/abstracts.aspx?aid=4631. (accessed Nov 28, 2011).
6 Baeton J, Celum C. Antiretroviral pre-exposure prophylaxis for HIV-1
prevention among heterosexual African men and women: The Partners PrEP
Study. 6th IAS Conference; July 17—20, 2011. Rome, Italy. Abstract
MOAX0106. http://pag.ias2011.org/flash.aspx?pid=886. (accessed Nov 28,
2011).
7 FEMem-PrEP Project. FHI360.
http://www.fhi.org/en/Research/Projects/FEM-PrEP.htm. (accessed Nov 28,
2011).
8 Baggaley RF, White RG, Boily M-C. HIV transmission risk through anal
intercourse: systematic review, meta-analysis and implications for HIV
prevention. Int J Epidemiol 2010; 39: 1048-1063.
9 Li H, Bar KJ, Wang S, et al. High multiplicity infection by HIV-1 in men
who have sex with men. PLoS Pathog 2010; 6: e1000890.
10 Brown KC, Patterson KB, Malone SA, et al. Single and multiple dose
pharmacokinetics of maraviroc in saliva, semen, and rectal tissue of
healthy HIV-negative men. J Infect Dis 2011; 203: 1484-1490.
11 Dumond JB, Patterson KB, Pecha AL, et al. Maraviroc concentrates in the
cervicovaginal fluid and vaginal tissue of HIV-negative women. J Acquir
Immune Defic Syndr 2009; 51: 546-553.
12 Patterson KB, Prince HA, Kraft E, et al. Penetration of tenofovir and
emtricitabine in mucosal tissues: implications for prevention of
HIV-1 transmission. Sci Transl Med 2011; 3: 112re4.
13 Berg KM, Arnsten JH. Practical and conceptual challenges in measuring
antiretroviral adherence. J Acquir Immune Defic Syndr 2006; 43 (suppl 1):
S79-S87.
14 Haberer J, Kahane J, Kigozi I, et al. Real-time adherence monitoring for
HIV antiretroviral therapy. AIDS Behav 2010; 14: 1340-1346.
15 Liu H, Miller LG, Hays RD, et al. A practical method to calibrate
self-reported adherence to antiretroviral therapy. J Acquir Immune Defic
Syndr 2006; 43 (suppl 1): S104-S112.

a UNC Center for AIDS Research Clinical Pharmacology and Analytical
Chemistry Core, Division of Pharmacotherapy and Experimental Therapeutics,
Eshelman School of Pharmacy, University of North Carolina at Chapel Hill,
Chapel Hill, NC 27599, USA b Center for Infectious Diseases, University of
North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

~~~~~~~~~~~~~~~~~~~
Andy Gray MSc(Pharm) FPS
* Senior Lecturer
Division of Pharmacology
Discipline of Pharmaceutical Sciences
School of Health Sciences
* Consultant Pharmacist
Centre for the AIDS Programme of Research in South Africa (CAPRISA)
University of KwaZulu-Natal PBag 7 Congella 4013 South Africa
Tel: +27-31-2604334/4298
Fax: +27-31-2604338
email: gra...@ukzn.ac.za or a...@gray.za.net

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