PrEP: PK modeling of daily TDF/FTC (Truvada) provides close to 100% protection against HIV infection

1 April 2012. Related: Conference reports, HIV prevention and transmission, CROI 19 (Retrovirus) 2012.

Simon Collins, HIV i-Base

Introduction

New research at CROI 2012 suggested that protection against HIV could be close to 100% from daily TDF/FTC (Truvada) and this should change previous reservations about PrEP as an intervention. [1]

In some studies, daily Truvada dramatically reduced the incidence of HIV infection, especially in high-risk individuals, (by 42% in MSM in the iPrEX study) but produced conflicting results in other studies (notably the FEM-PrEP study in heterosexual African women).

All studies have proved complicated to interpret due to the high rates of self-reported adherence but the likely very low rates of actual adherence demonstrated in PK sub-studies finding low levels of tenofovir and FTC in both active and placebo arms. The projected efficacy of PrEP increased dramatically when PK results were taken into account (to 92% in iPrEX). [2]

This proven protection could potentially increase real-life adherence compared to that seen in historical studies. If someone knows they will be protected rather than being a participant in a placebo controlled trial, and that this protection is so effective it could eliminate the risk of HIV, this could change the pattern of low use, even in less adherent patients.

PrEP studies are further complicated by the differences in pharmacokinetic properties of individual drugs, by differences in absorption of each drug in the male and female genital tract as well as in rectal tissue, and by the intracellular concentration of the active metabolites at each sites. Differences between human and animal drug absorption may limit how closely efficacy against vaginal and rectal exposure can be interpreted from macaque studies.

At CROI new modeling data showed that the protection from PrEP may be even greater than previously thought. The report that protection approaches 100% argues for new considerations for how PrEP might be incorporated as a health intervention.

Other studies at the meeting addressed some of the concerns for why PrEP has not been universally protective in other some studies.

iPrEX: modeled prediction of 99% protection with daily adherence

Peter Anderson and colleagues presented a late breaker oral PK analysis of intracellular drug concentrations in the iPrEX study and correlated this with levels of adherence in the Strand Study. [1]

This group used regression model to estimate efficacy of PrEP based on intracellular levels of tenofovir diphosphate (TDF-DP) in viable PBMCs from 48 cases matched to 144 uninfected controls. The researchers then established TDF-DP levels achieved on observed therapy of 2, 4 and 7 day dosing in a separate PK study of 24 HIV negative volunteers (the Strand study). Finally, they used the iPrEX regression models from i-PrEX on the Strand study data to estimate PrEP efficacy based on 2, 4 and 7 day dosing.

In iPrEX, detectable tenofovir levels in either plasma or cells was seen to have steadily fallen from baseline to time of infection, to only 8% of cases (at infection) compared to approximately 40% of uninfected controls. In the month prior to infections these rates were 11% vs 50% respectively suggesting that infections occurred during periods of low drug exposure.

In the Strand study, dosing 2, 4 and 7 days a week produced median (IQR) levels (fmol/million cells) of TDF-DP of 11 (6-13), 32 (25-39) and 42 (31-47) respectively. This compared to levels of 11 fmol/M (4-11) in 8% of iPrEX cases with detectable TDF and 16 fmol/M (9-47) in the 44% of controls with detectable levels. Daily dosing could be imputed from drug levels for 18% of iPrEX controls (and that 82% controls were likely to be taking less than daily dosing).

Regression modelling produced and estimated EC90 of 16 fmol/M viable cells (95%CI 3-28) with sensitivity estimates of less than 23 fmol/M producing estimates for risk reduction of 76% (56-96%), 96% (90->99%) and 99% (96->99%) for 2, 4 and 7 day dosing (see Table 1).

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This study involved 615 v-PBMC and 1146 plasma samples tested from 1212 time points (302 cases, 910 controls). Limitations include that drug levels were only proximal to time of exposure and that the impact of FTC levels were not studied.

The confidence intervals for the target IC90 of ≥15.6 fmol/M viable cells (95%CI 3.0 to 28.2) appears wide and this should be confirmed in future studies.

Partners PrEP: protection in serodifferent heterosexual couples

Jared Beaten and colleagues presented updated results from the randomised Partners PrEP Study, a randomised placebo controlled study of both TDF/FTC and TDF only in 4758 negative partners of HIV positive people who were not yet eligible for ARV therapy. [3]

The study was conducted in nine urban and rural sites in Kenya and Uganda. HIV negative partners were seen monthly for HIV testing, adherence and prevention counselling and HIV positive partners were seen every three months and approximately 20% in each arm started ARV treatment when recommended by national guidelines.

The placebo arm was discontinued in July 2010 following a recommendation by the study DSMB and those preliminary results had already been presented. Placebo arm participants were then randomised to either of the active arms and follow up continues until December 2012.

Approximate baseline characteristics for the negative partner included: just over 60% male; median (IQR) age 33 years (28, 40; with 11% less than 25 years). Although the median (IQR) duration of partnership was 7 years (3, 14) the time they had know about their partners HIV status was only 4-5 months (0.1, 2.0 years). Median CD4 count of the positive partner was almost 500 cells/mm3 (IQR 375, 660).

Study retention was greater than 95% with median follow up of 23 months (IQR 16 – 28, range 1-36). This involved more than 7800 person years of follow up (PYFU) and >99,000 study visits, with >95% dispensing of study meds.

Of the 96 new HIV diagnoses in negative partners, 14 were found to be in acute infection at baseline by retrospective PCR testing after HIV seroconversion, leaving 82 acquisition events in the primary study. Of these, 17 occurred in the TDF arm vs 13 in the TDF/FTC arm vs 52 in the placebo arm giving incidence rates/100 PYFU of 0.65, 0.50 and 1.99 respectively. This produced highly significant protection rates of 67% (95%CI 44-81%) and 75% (95%CI 55-87%) compared to placebo, in the TDF and TDF/FTC arms respectively (both p<0.0001). There were no significant differences between the two active arms (p=0.23) and both ruled out the predefined lower efficacy of -30%.

Although 60% of the negative partners were men, 45/82 infections occurred in women (n= 8 vs 9 vs 28; incidence 2.81 in women vas n=9, 4 and 24; incidence 1.49 in men; in single vs dual vs placebo arms respectively. Protection was seen for both men and women with non statistically significant differences for the differences in the results observed in men vs women (p=0.65 for single and p=0.24 for dual PrEP (see Table 2)

There were no differences between serious adverse events between arms including placebo (7% each arm) or confirmed laboratory abnormalities (each arm had <1% grade 2 or higher creatinine increase, 9% phosphorus decrease). During the first month there was significantly more mild nausea or fatigue in the active arms but these became similar to placebo rates at later time points.

Although there was one person with K65R tenofovir mutation and one person with M184V FTC mutation in the people with confirmed acute infection at baseline, no mutations were detected in infections from the main study. Four cases of NNRTI resistance was seen indication transmission of resistant virus.

About one third of participants reported additional sexual partners (41% men, 9% women)

PK results for drug levels of tenofovir in each of the active arms in the Partners in PrEP study were presented in a second oral presentation by Deborah Donnell. [4]

This study used the 29 cases (n=17 single arm, n=12 dual arm) compared to drug levels in 100 uninfected controls from each arm, using multiple samples throughout the study (at months 1, 3, 6, 12, 18, 24, 30, and 36. Drug levels were tested using LCMS with lower limit of quantification of 0.3 ng/mL. Based on other studies tenofovir would be detected for nine days after a single dose and tenofovir levels at steady state from daily dosing would be >40 ng/mL.

Tenofovir was detected in >80% of samples in uninfected controls compared to 56% of samples of cases and in only 31% (6/17) of single arm and 25% (3/12) of dual arm samples at the seroconversion visit. This produced relative risk reduction associated with detectable drug of 86% (95%CI 57%, 95%; p<0.001) and 90% (95%CI 56%, 98%; p=0.002) in the single and dual arms respectively. Only 4/9 cases of infections with detectable drug had levels > 40 ng/mL consistent with high adherence.

Patterns of adherence in controls suggested than non- or poorly adherent patients did not change their adherence of the study. By contrast, about 50% of highly adherent patients maintained this through the study but 25% either dropped to lower adherence and 25% to non-adherence.

Several other analyses were presented from the Partners in PrEP study at CROI. These included:

• A report on nearly 300 pregnancies during the study, with similar rates in each of the three arms and no safety concerns, and suggesting a specific use for PrEP in serodifferent couples wanting to have a baby. [5]
• Details of ARV update in the 817 positive partners whose CD4 count declined during the study making them eligible to start treatment, with only 420 (55%) initiating treatment. Factors included reluctance to start, loss to follow up and unavailability of treatment. [6]
• High (>90%) positive acceptance to use PrEP amongst negative partners with lower, but still high (60%) interest from positive partners in earlier treatment as prevention. [7]
• Implications from PrEP protection on the rate of false positive results from rapid tests. From over 99,000 tests, 266 were positive on dual rapid tests. Of these, 37% (99/266) were confirmed true positive by ELISA, 58% (155/266) were false positive by ELISA and 4.5% (12/266) were indeterminate. False positives were more common in the active arms 69% (110/159) vs 45% (45/107) in the placebo arm due to the lower incidence of HIV. [8]
• Modelling factors for a risk score to determine the population characteristics for most effective use of PrEP as an intervention. [9]

Why PrEP did not work in FEM-PrEP

Another late breaker oral presentation provided results from the FEM-PrEP study in which daily TDF/FTC (Truvada) used as PrEP was not effective. The FEM-PrEP study, which had enrolled just over 2000 of the planned 3900 participants was closed in April 2011 due to lack of efficacy between daily TDF/FTC compared to placebo in over 2000 African heterosexual women.

The DSMB recommended stopping the study when the study was only half way through enrollment when 28 infections had been seen in each arm. More pregnancies occurred and side effects were also higher in the active arm.

The final results from the study were presented at CROI by Lut Van Damme and colleagues. [10]

Baseline characteristics included approximately 60% younger than 25 years, 50% condom use, 13% had transactional sex with other than primary partners. However, 70% of participants thought they were at low risk for HIV, but 15% had Chlamydia and 6% had gonorrhoea at screening. Women had sex on average four times a week (mean 3.7, range 0-28).

Of 68 infections occurring during the main study, 33 infections occurred in the active arm (incidence rate, 4.7/100 person-years) and 35 in the placebo group (IR, 5.0/100 person-years), with an estimated hazard ratio (HR) for infection of 0.94 (95%CI 0.59 to 1.52, p = 0.81). Although seven infections were discounted due to lack of product at the study clinic, a sensitivity analysis censuring women at last date of product use did not change the main results (HR 0.82; 95%CI 0.49-1.36, p=0.44).

Tolerability generally good with no grade 3 events but included more nausea in the active group.

There were five cases of FTC-associated resistance (one in the placebo arm) but no cases of resistance to TDF.

As with other PrEP studies, adherence rates were very high by self-report (>95%) and pill count (~90%) but a pharmacokinetic analysis in a case-control sub study indicated that this was at best likely to be 20-30% in either arm, with detection lower in cases vs controls. Adherence levels below 50% in each arm also removed the power of this study to be able to detect a real impact of the active arm.

Of interest, an opinion piece by Anneke Grobler and colleagues in the 13 March edition of AIDS on the design challenges for future prevention studies includes a table that calculates projected effectiveness found with different levels of true efficacy of the comparator and new intervention in combination with different adherence levels. [11]

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Although the lack of protection in this study was assigned to low adherence, this may be more complex as adherence was also low in iPrEX. This may also involve the baseline risk of participants and perception of risk, perhaps explaining the differences seen in other heterosexual studies such as TDF-2.

There may also be implications by gender related to pharmacokinetic and intermittent adherence highlighted in macaque studies, including the poster reported below.

Intermittent TDF/FTC (Truvada) in macaques: vaginal, cervical and rectal tissue and cell PK

Jessica Radzio and colleagues from the CDA in Atlanta presented results from a pharmacokinetic study in macaques. [12]

This study was important for studying both tenofovir and FTC in tissue site and intracellular levels. Both drugs peaked – at two hours in plasma and five hours in vaginal secretions – and then declined to low levels at 24 hours. In rectal secretions, levels increased more slowly and steadily, only peaking at 24 hours but then remaining high for at least 24 hours.

This aspect of the PK profile in macaques is comparable to that seen in women. The group then looked at active intracellular levels of the active metabolites of each drug, FTC-TP and TFV-DP.

FTC drug levels were very similar in vaginal, cervical, rectal and lymphoid tissue compared to cell biopsies with vaginal:rectal ratio of 1.04 in cells and 2.10 in tissue at 24 hours. This was similar for cervical:rectal ratios. However levels of tenofovir in vaginal, cervical and lyphoid tissue, both in tissue and cells was dramatically lower, while remaining high in rectal tissue and cells, with vaginal:rectal tissue concentrations ratios dropping to 0.04 for intracellular levels and 0.02 in tissue, with similar results for cervical:rectal ratios (0.04 and 0.03 respectively).

The group then looked at whether these levels would be sufficient for vaginal exposure in six macaques following oral dosing and repeat low dose exposure weekly for up to 18 weeks (through four menstrual cycles) to SIV to approximate to human sexual exposure, with six macaque controls. TDF/FTC or placebo was given 24 hours before or two hours after exposure. All control animals became infected quickly, mainly in the first menstrual cycle but none of the active macaques receiving intermittent TDF/FTC became infected over 18 weeks suggesting that the lower PK may be protective even with intermittent PrEP to prevent vaginal transmission.

This study reported a pattern of ratio (rather than absolute concentrations) suggesting this validates the macaque model for future studies. Although this study only looked at -24 plus +2 hour dosing for vaginal exposure, the rectal macaque studies emphasised the +2 hour dose to be essential and the protection from the pre-exposure dose extended from 1 to seven days. However dosing only 2 hours before exposure correlated with significantly reduced protection, though this was still higher than if no pre-exposure dose was given.

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The potential for close to 100% protection against HIV infections with alternate or daily dosing should prompt pilot programmes that include access to this option in individuals who are at the highest risk for HIV.

For many people, higher risk behaviour and vulnerability to infection may be associated with a relatively short period of someone’s life. Whether this is a period of weeks, months or several years, the option to use an oral prophylaxis when other prevention methods are unlikely to be used, can prevent the complications of life-long infection and treatment.

TDF/FTC (Truvada) has already been submitted to the FDA for an indication for use as PrEP with a decision expected later this year.

References

Unless stated otherwise, all references are to the Programme and Abstracts for the 19th Conference of Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle.

1. Anderson P et al. Intracellular tenofovir-DP concentrations associated with PrEP efficacy in MSM from iPrEx. 19th CROI 2012, Seattle. Oral late breaker abstract 31LB.
   http://www.retroconference.org/2012b/Abstracts/45431.htm
2. Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. NEJM. 23 November 2010 (10.1056/NEJMoa1011205). Free access:
   http://www.nejm.org/doi/full/10.1056/NEJMoa1011205
3. Baeten J et al. ARV PrEP for HIV-1 prevention among heterosexual men and women. 19th CROI 2012, Seattle. Oral abstract 29.
   http://www.retroconference.org/2012b/Abstracts/43082.htm
4. Donnell D et al. Tenofovir disoproxil fumarate drug levels indicate PrEP use is strongly correlated with HIV-1 protective effects: Kenya and Uganda. 19th CROI 2012, Seattle. Oral abstract 30.
   http://www.retroconference.org/2012b/Abstracts/43156.htm
5. Mugo N et al. Pregnancy Incidence and birth outcomes among in a clinical trial of PrEP: Uganda and Kenya. 19th CROI 2012, Seattle. Poster abstract 1060.
   http://www.retroconference.org/2012b/Abstracts/43083.htm
6. Mujugira A et al. Barriers to ART initiation among HIV-1+ individuals: East Africa. 19th CROI 2012, Seattle. Poster abstract 649.
   http://www.retroconference.org/2012b/Abstracts/43075.htm
7. Heffron R et al. Preferences for and willingness to use ARV-based HIV-1 prevention strategies among HIV-1 serodiscordant couples: Kenya. 19th CROI 2012, Seattle. Poster abstract 1065.
   http://www.retroconference.org/2012b/Abstracts/43127.htm
8. Ndase P et al. Frequency of false positive HIV rapid tests in a cohort of men and women receiving PrEP—implications for programmatic roll-out: Kenya and Uganda.19th CROI 2012, Seattle. Poster abstract 1058.
   http://www.retroconference.org/2012b/Abstracts/43085.htm
9. Kahle E et al. An empiric risk-scoring tool for identifying high-risk heterosexual HIV-1 serodiscordant couples for targeted HIV-1 prevention. 19th CROI 2012, Seattle. Poster abstract 1102.
   http://www.retroconference.org/2012b/Abstracts/43883.htm
10. Van Damme L et al. The FEM-PrEP trial of emtricitabine/tenofovir disoproxil fumarate (Truvada) among African women. 19th CROI 2012, Seattle. Oral late breakerabstract 32LB.
    http://www.retroconference.org/2012b/Abstracts/45406.htm
11. Grobler AC, Abdool Karim SS. AIDS: 13 March 2012 – Volume 26 – Issue 5 – p 529–532.
    http://journals.lww.com/aidsonline/Fulltext/2012/03130/Design_challenges_facing_clinical_trials_of_the.1.aspx
12. Radzi J et al. Intermittent oral PrEP with Truvada prevents vaginal SHIV transmission in macaques. 19th CROI 2012, Seattle. Poster abstract 1086.
    http://www.retroconference.org/2012b/Abstracts/42869.htm