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Dramatic Increase in Use of Oral TDF/FTC for PrEP in the U.S. -- Plus a Few Cautions

March 3, 2016

Dozens of studies at CROI 2016 reported an overwhelmingly positive impact of TDF/FTC, which is currently the only FDA-approved HIV medicine with a PrEP indication.

The most optimistic of these studies covered scale up programmes that are transforming approaches to HIV prevention. When taken daily, oral TDF/FTC works, preventing infections with a close to 100% efficacy.

Event-driven or "as needed" dosing -- although not approved -- is also an increasingly widely used approach but requires doses both before and after sex (as in the IPERGAY study).


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Uptake and Roll-Out

Many of the studies are from the U.S., where TDF/FTC has been approved as PrEP since 2012 -- including uptake in high incidence urban settings including San Francisco, Boston, New York and Washington.1-5

Although U.S. uptake was originally slow, the most rapid increase in use has been in the last two years to more than 40,000 people -- though this is still early days in terms of potential use. Many of these studies include problems of drug access even with assistance programmes in the U.S. that provide PrEP free.

Many emphasised community initiatives, including an impressive overview by long-term prevention activist Jim Pickett using examples globally and from programmes in Chicago. Many of these approaches normalise PrEP -- similar to sun-lotion -- some not even mentioning HIV. Essential viewing.6

Other studies highlighted cautions, generally minor compared to the achievement of prevention and goal of cutting HIV incidence. Higher STI rates were sometimes reported -- but these studies were often uncontrolled and ignored the increasing incidence that predated PrEP. Increased reporting of STIs is balanced, including by higher rates of detection and treatment, including in the UK, because of more frequent routine monitoring.7

Many U.S. studies recommended more frequent STI monitoring -- from every 6 months in current U.S. CDC guidelines to every 3 months that has been standard in European studies.8,9

Other studies looking at practical issues relating to the delivery of PrEP included the use of rapid tests to confirm initial negative status, and also the increased chance of detecting recent infections using 4th generation HIV tests and perhaps viral load in cases or recent high risk.10-12


Case Report of HIV Infection on PrEP Due to Drug Resistance

It has always been known that PrEP only works when the drugs are sensitive to HIV. PrEP failure due to drug resistance even in the context of good adherence was always possible -- and the first case was reported at CROI 2106.

In this example, a gay man was unfortunately infected with multidrug resistant HIV, including to TDF/FTC -- and the case was widely reported as one of the leading news stories. Baseline resistance testing shown multiple NRTI, NNRTI and integrase associated mutations.13

This case is important for being reported on a community PrEP discussion group and for being the first well-documented example. Estimating the resulting impact this has on overall PrEP efficacy is difficult, but the denominator would be based both on number of overall PrEP exposures (rather than number of people using PrEP), together with the background incidence of drug resistance in that setting.

Taken together, these cases are likely to continue to be very rare, especially in the context of the overwhelmingly positive effect PrEP is having on reducing HIV infections and improving quality of life.

Luckily population rates of drug resistance to TDF/FTC in are currently low in countries where rates of viral load suppression on ART are high and where viral load monitoring on ART is routine.

In the UK for example, low level resistance to either drugs was <1% in newly diagnosed individuals and high level resistance to both drugs (ie with K65R plus M184V mutations in RT), was only detected at 0.1% in the analysis from 2013/14.14


Safety Issues With TDF/FTC

Safety results are holding up surprisingly well with TDF/TFC, with low incidence of serious side effects, but this is again dependent on routine monitoring.

When side effects occur, the plausible association with both adherence and dose/absorption was highlighted in several studies. For example, incidence of side effects is underestimated in many PrEP studies by low adherence and two poster reported greater reductions in renal function, with drug levels.

Monica Gandhi from UCSF reported that tenofovir levels in hair samples correlated with the risk of reduced eGFR in a subset of 200 men from the open label phase of the IPrEX study. Over 18 months, the mean percentage reduction in eGFR from baseline was 2.6ml/min (SE 0.8) vs 5.6 (SE 0.7), for those with tenofovir levels in the first vs fourth quartiles [OR 4.4 (95%CI: 1.1 to 17.4), with p = 0.045 for trend]. Reduced eGFR was also associated with lower CrCl <90 mL/min and older age (>40 years).15

A similar dose relationship was reported trom the U.S. Demo Project with greater decline in CrCl associated with drug levels linked to >4 doses a week (approximately 5% over the first 12 weeks and stable thereafter).16

In the heterosexual African Partners PrEP study, proximal tubulopathy was rare and occurred at similar rates in the active and placebo groups, although one case of Fanconi's syndrome related to TDF was reported in a person using other nephrotoxic drugs.17

Reductions in bone density in a sub-group of participants in the iPrEX study were also significantly greater in participants with tenofovir diphosphate levels associated with taking four or more doses a week (>16 fmol/m), compared to people in the placebo group. In the subset of participants with multiple DEXA results, these changes reversed during the interruption in PrEP between the end of the main study and access in the open label phase.18

While overall tolerability was good, the dose relationship of both kidney and bone toxicity with TDF/FTC levels suggests benefits of event-based dosing strategies such as the IPERGAY study.19,20

It also suggests advantages for tenofovir alafenamide (TAF) if it is proven to have PrEP activity. This is not yet clear because while a macaque study was exciting for showing 100% protection against repeated rectal exposure, a single-dose PK study in HIV negative women reported either low or undetectable levels of tenofovir diphosphate in vaginal and rectal tissue.21,22

These two results are difficult to reconcile unless levels in tissue are not directly related to the protective mechanism for PrEP, with the intracellualr levels in lymph cells being crucial.


Comment

The regulatory decision for TDF/FTC for PrEP in Europe is still being reviewed.

A decision about NHS access in the UK is not expected until June 2016.


References

Unless stated otherwise, all references are to the Programme and Abstracts of the Conference on Retroviruses and Opportunistic Infections, 22-25 February 2016, Boston, USA.

  1. Hare C et al. Delivery of PrEP: from evidence to practice. 23rd CROI 2016, Boston. Oral abstract 68.
    www.croiwebcasts.org/console/player/29560 (Webcast)
  2. Scanlin KK et al. Increasing PrEP use among men who have sex with men, New York City, 2013-2015. 23rd CROI 2016, Boston. Poster abstract 888.
    www.croiconference.org/sessions/increasing-prep-use-among-men-who-have-sex-men-new-york-city-2013-2015
  3. Delaney KP et al. Awareness and use of PrEP appear to be increasing among internet samples of U.S. MSM. 23rd CROI 2016, Boston. Poster abstract 889.
    www.croiconference.org/sessions/awareness-and-use-prep-appear-be-increasing-among-internet-samples-us-msm
  4. Mayer KM et al. Increasing HIV suppression, PrEP use, and STDs in Boston MSM accessing primary care. 23rd CROI 2016, Boston. Poster abstract 889.
    www.croiconference.org/sessions/increasing-hiv-suppression-prep-use-and-stds-boston-msm-accessing-primary-care
  5. Levy ME et al. Correlates of uptake of HIV prevention interventions among black MSM in DC, 2013-2014. 23rd CROI 2016, Boston. Poster abstract 893.
    www.croiconference.org/sessions/correlates-uptake-hiv-prevention-interventions-among-black-msm-dc-2013-2014
  6. Pickett J. PrEP-4-Love: transmitting desire across Chicago. 23rd CROI 2016, Boston. Oral abstract 70.
    www.croiwebcasts.org/console/player/29562 (Webcast)
  7. McCormack S et al, Sexually transmitted infection control in the era of PrEP. 23rd CROI 2016, Boston. Oral abstract 69.
    www.croiwebcasts.org/console/player/29561 (Webcast)
  8. Cohen S et al. Quarterly STI screening optimizes STI detection among PrEP users in the Demo Project. 23rd CROI 2016, Boston. Poster abstract 70.
    www.croiconference.org/sessions/quarterly-sti-screening-optimizes-sti-detection-among-prep-users-demo-project
  9. Golub SA et al. STI data from community-based PrEP implementation suggest changes to CDC guidelines. 23rd CROI 2016, Boston. Poster abstract 869.
    www.croiconference.org/sessions/sti-data-community-based-prep-implementation-suggest-changes-cdc-guidelines
  10. Delaugerre C et al, Usefulness of rapid tests for HIV diagnosis in the ANRS IPERGAY PrEP trial. 23rd CROI 2016, Boston. Poster abstract 522.
    www.croiconference.org/sessions/usefulness-rapid-tests-hiv-diagnosis-anrs-ipergay-prep-trial
  11. Livant et al. 4th generation rapid tests improve detection of acute infection in MTN-003 (VOICE). 23rd CROI 2016, Boston. Poster abstract 521.
    www.croiconference.org/sessions/4th-generation-rapid-tests-improve-detection-acute-infection-mtn-003-voice
  12. Bacon et al. HIV Testing in the U.S. PrEP Demonstration Project: rEIA vs antigen/antibody vs RNA. 23rd CROI 2016, Boston. Poster abstract 524.
    www.croiconference.org/sessions/hiv-testing-us-prep-demonstration-project-reia-vs-antigenantibody-vs-rna
  13. Knox C et al. HIV-1 infection with multiclass resistance despite preexposure prophylaxis (PrEP). 23rd CROI 2016, Boston. Late-breaker poster abstract 479aLB.
    www.croiconference.org/sessions/hiv-1-infection-multiclass-resistance-despite-preexposure-prophylaxis-prep
  14. Tostevin A et al. Trends in transmitted drug resistance to HIV-1 in the UK since 2010. BHIVA annual conference, 21-24 April 2015, Brighton.
    www.bhiva.org/documents/Conferences/2015Brighton/Presentations/150423/AnnaTostevin.pdf (PDF)
  15. Gandhi M et al. Higher cumulative TFV/FTC levels in PrEP associated with decline in renal function. 23rd CROI 2016, Boston. Poster abstract 866.
    www.croiconference.org/sessions/higher-cumulative-tfvftc-levels-prep-associated-decline-renal-function
  16. Liu AY et al. Changes in renal function associated with TDF/FTC PrEP use in the U.S. Demo Project. 23rd CROI 2016, Boston. Poster abstract 867.
    www.croiconference.org/sessions/changes-renal-function-associated-tdfftc-prep-use-us-demo-project
  17. Mugwanya KK et al. Rare incidence of proximal tubular dysfunction with tenofovir-based chemoprophylaxis. 23rd CROI 2016, Boston. Poster abstract 886.
    www.croiconference.org/sessions/rare-incidence-proximal-tubular-dysfunction-tenofovir-based-chemoprophylaxis
  18. Grant R et al. Recovery of bone mineral density after stopping oral HIV preexposure prophylaxis. 23rd CROI 2016, Boston. Late breaker oral abstract 48LB.
    www.croiwebcasts.org/console/player/29449 (Webcast)
  19. Molina JM et al. On demand PrEP with oral TDF-FTC in MSM: results of the ANRS IPERGAY trial. 23rd CROI 2016, Boston. Oral abstract 22LB.
    www.croiwebcasts.org/console/player/25540 (Webcast)
  20. Molina JM et al. On demand PrEP with oral TDF-FTC in the open-label phase of the ANRS IPERGAY trial. 23rd CROI 2016, Boston. Poster abstract 886.
    www.croiconference.org/sessions/demand-prep-oral-tdf-ftc-open-label-phase-anrs-ipergay-trial
  21. Massud I et al. Chemoprophylaxis with oral FTC/TAF protects macaques from rectal SHIV infection. 23rd CROI 2016, Boston. Oral abstract 107.
    www.croiwebcasts.org/console/player/29582 (Webcast)
  22. Garrett KL et al. TFV and TFVdp in female mucosal tissues after a single dose of TAF. 23rd CROI 2016, Boston. Oral late breaker abstract 102LB.
    www.croiwebcasts.org/console/player/29628 (Webcast)



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