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Tenofovir Disoproxil Fumarate Fails to Prevent HIV Acquisition or the Establishment of a Viral Reservoir: Two Case Reports

The use of antiretrovirals as pre-exposure prophylaxis (PrEP) is highly efficacious in HIV prevention. The World Health Organization recently recommended Truvada® (Gilead Sciences, Inc.) or tenofovir disoproxil fumarate (TDF) for high-risk individuals, with limited data for single-agent TDF PrEP in men who have sex with men (MSM). We report two cases of TDF PrEP failure in MSM who had received long-term TDF for hepatitis B infection and had therapeutic levels of drug immediately after HIV acquisition. Rapid antiretroviral intensification at diagnosis of acute HIV infection failed to limit immune dysfunction or prevent the establishment of a viral reservoir. Electronic supplementary material The online version of this article (doi:10.1007/s40121-015-0102-x) contains supplementary material, which is available to authorized users.


INTRODUCTION
The use of antiretrovirals (ARVs) as pre-exposure prophylaxis (PrEP) is highly efficacious at limiting HIV transmission [1][2][3][4][5][6] [7]. Single-agent TDF PrEP shows benefit over placebo and is comparable with Truvada in preventing HIV transmission in HIV serodiscordant heterosexual couples [2] and individuals who inject drugs [3]. Efficacy data for TDF in men who have sex with men (MSM) are limited [8] and it is not known whether drug level requirements are the same for both HIV treatment and prevention. However, animal model data suggest that TDF alone is less protective than Truvada [9,10] and pharmacokinetic analysis of the partners PrEP study supports this [11]. Cases of PrEP failure mainly occur due to poor adherence [1][2][3][4][5][6]11]. Early detection is essential to minimize monotherapy drug exposure and prevent drug resistance development [12]. Whether ARV therapy (ART) should be stopped or intensified at PrEP failure is unclear [13]. A recent case presentation reported an undetectable viral reservoir in an individual's intensifying ART at PrEP failure [14]. This is supported by cohort data and data from macaques suggest that three-drug ARV at acute HIV infection can improve clinical outcome [15][16][17] by limiting viral reservoir [17][18][19][20] and immune dysfunction [21][22][23], and that these benefits are greater the earlier the ARVs are started [15][16][17].

HIV Reservoir
Purified CD4 T cells were analyzed by qPCR for HIV-1 DNA (total and integrated) and cell-associated HIV-1 RNA unspliced transcripts (CA-RNA) as reported elsewhere [19].

Immune Activation and Exhaustion
PBMC were stained with the anchor markers

DISCUSSION
As PrEP is becoming more widely available and uptake increasing, this is a timely reminder that TDF monotherapy PrEP in MSM has limited efficacy data and that HIV-1 acquisition can occur in the presence of TFV drug levels within the therapeutic range required to treat HIV [26].
These cases are instructive to providers and the field of PrEP, and highlight that patients with HBV receiving tenofovir for HBV should consider intensification to Truvada (TDF/FTC) if they meet guidelines (e.g., Centers for Disease Control and Prevention) for PrEP. The lack of resistance detected concurs with randomized control study data showing a very low incidence of resistance in cases of tenofovir failure [29]. Although PrEP effectiveness is largely driven by adherence [1-8, 11, 26, 27] [12]. These cases also show that rapid intensification with ARVs did not prevent reservoir seeding or immune dysfunction. Indeed, the level of viral reservoir, immune activation, and immune exhaustion were comparable to those observed in untreated primary HIV cohorts [15]. Patient A is of additional interest as this occurred despite no evidence of on-going viral replication in plasma prior to ARV intensification. This suggests the importance of sanctuary sites for the establishment of viral reservoir and is consistent with primate models [27].

CONCLUSION
Single-drug TDF PrEP was not effective in preventing HIV infection and intensified ART post-infection did not reduce the viral reservoir in either patient. Whilst single-agent PrEP is not to be recommended as an HIV prevention strategy in MSM in European [28] and US [13] PrEP guidelines, it is by the WHO [7]. Close monitoring of outcomes of TDF usage in MSM needs to be carried out.

ACKNOWLEDGMENTS
We would like to thank the Kings College London Infectious Diseases Biobank. No funding was received for publication of this article. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.
Disclosures. Julie Fox has received research