Pre-Exposure Prophylaxis to Prevent the Acquisition of HIV-1 Infection (PROUD): Effectiveness Results from the Pilot Phase of a Pragmatic Open-Label Randomised Trial

BACKGROUND:

Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir-emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect.

METHODS:

PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986).

FINDINGS:

We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64-96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3-11·3). 13 men (90% CI 9-23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEP. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients.

INTERPRETATION:

In this high incidence population, daily tenofovir-emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection.

Below:  Trial profile

*First to deferred and subsequently to immediate; considered in the deferred group for analyses but continued on pre-exposure prophylaxis. †19 pairs of partners were allocated to the same group (14 to immediate, five to deferred) including six pairs (all assigned to the immediate group) not enrolled concurrently. ‡One participant who was allocated to the deferred group was prescribed immediate pre-exposure prophylaxis in error; he was included in the deferred group for analyses but continued on pre-exposure prophylaxis. §Includes unable to contact, moved away, and non-attendance as no longer at risk. ¶HIV status ascertained if confirmed HIV-positive or HIV-negative test after 48 weeks or after Oct 13, 2014.

Full article at:   http://goo.gl/JzMn11

By:  McCormack S1, Dunn DT2, Desai M3, Dolling DI2, Gafos M2, Gilson R4, Sullivan AK5, Clarke A6, Reeves I7, Schembri G8, Mackie N9, Bowman C10, Lacey CJ11, Apea V12, Brady M13, Fox J14, Taylor S15, Antonucci S16, Khoo SH17, Rooney J18, Nardone A19, Fisher M6, McOwan A16, Phillips AN20, Johnson AM20,Gazzard B5, Gill ON19.

• 1MRC Clinical Trials Unit at UCL, London, UK; 56 Dean Street, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK. Electronic address: s.mccormack@ucl.ac.uk.
• 2MRC Clinical Trials Unit at UCL, London, UK.
• 3MRC Clinical Trials Unit at UCL, London, UK; HIV & STI Department, Public Health England Centre for Infectious Disease Surveillance and Control, London, UK.
• 4The Mortimer Market Centre, Central and North West London NHS Foundation Trust, London, UK; Research Department of Infection and Population Health, University College London, London, UK.
• 5St Stephen's Centre, Chelsea and Westminster Healthcare NHS Foundation Trust, London, UK.
• 6Claude Nicol Centre, Royal Sussex County Hospital, Brighton & Sussex University Hospitals NHS Trust, Brighton, UK.
• 7Homerton University Hospital NHS Foundation Trust, London, UK.
• 8Manchester Centre for Sexual Health, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
• 9St Mary's Hospital, Imperial College Healthcare NHS Foundation Trust, London, UK.
• 10Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
• 11York Teaching Hospital and Hull York Medical School, University of York, York, UK.
• 12Ambrose King Centre and Barts Sexual Health Centre, Barts Health NHS Trust, London, UK.
• 13King's College Hospital NHS Foundation Trust, London, UK.
• 14Guy's and St Thomas' NHS Foundation Trust, London, UK.
• 15Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, UK.
• 1656 Dean Street, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
• 17University of Liverpool, Liverpool, UK.
• 18Gilead Sciences Foster City, CA, USA.
• 19HIV & STI Department, Public Health England Centre for Infectious Disease Surveillance and Control, London, UK.
• 20Research Department of Infection and Population Health, University College London, London, UK. 
• Lancet. 2016 Jan 2;387(10013):53-60. doi: 10.1016/S0140-6736(15)00056-2. Epub 2015 Sep 9.

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Trends & Determinants of Survival for Over 200, 000 Patients on Antiretroviral Treatment in the Botswana National Program: 2002–2013

Objectives:

To determine the incidence and risk factors of mortality for all HIV-infected patients receiving antiretroviral treatment at public and private healthcare facilities in the Botswana National HIV/AIDS Treatment Programme.

Design:

We studied routinely collected data from 226 030 patients enrolled in the Botswana National HIV/AIDS Treatment Programme from 2002 to 2013.

Methods:

A person-years (P-Y) approach was used to analyse all-cause mortality and follow-up rates for all HIV-infected individuals with documented antiretroviral therapy initiation dates. Marginal structural modelling was utilized to determine the effect of treatment on survival for those with documented drug regimens. Sensitivity analyses were performed to assess the robustness of our results.

Results:

Median follow-up time was 37 months (interquartile range 11–75). Mortality was highest during the first 3 months after treatment initiation at 11.79 (95% confidence interval 11.49–12.11) deaths per 100 P-Y, but dropped to 1.01 (95% confidence interval 0.98–1.04) deaths per 100 P-Y after the first year of treatment. Twelve-month mortality declined from 7 to 2% of initiates during 2002–2012. Tenofovir was associated with lower mortality than stavudine and zidovudine.

Conclusion:

The observed mortality rates have been declining over time; however, mortality in the first year, particularly first 3 months of antiretroviral treatment, remains a distinct problem. This analysis showed lower mortality with regimens containing tenofovir compared with zidovudine and stavudine. CD4⁺ cell count less than 100 cells/μl, older age and being male were associated with higher odds of mortality.

Below:  Distribution of yearly deaths by duration of treatment.

Below:  Mortality rate in the first year after treatment initiation

Full article at:   http://goo.gl/cNxJNs

By:  Mansour Farahani,a Natalie Price,a Shenaaz El-Halabi,b Naledi Mlaudzi,b Koona Keapoletswe,b Refeletswe Lebelonyane,b Ernest Benny Fetogang,b Tony Chebani,a Poloko Kebaabetswe,c Tiny Masupe,c Keba Gabaake,c Andrew Auld,d Oathokwa Nkomazana,c and Richard Marlinka

^aHarvard T.H. Chan School of Public Health, Boston, Massachusetts, USA

^bMinistry of Health

^cUniversity of Botswana, Gaborone, Botswana

^dCenter for Disease Control and Prevention, Atlanta, Georgia, USA.

Correspondence to Mansour Farahani, MD, MPH, ScD, Harvard School of Public Health, Boston, MA, USA. E-mail:

AIDS. 2016 Jan 28; 30(3): 477–485.

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Hepatitis B Virus (HBV) Variants in Untreated and Tenofovir Treated Chronic Hepatitis B (CHB) Patients during Pregnancy and Post-Partum Follow-Up

Chronic hepatitis B (CHB) is a dynamic disease that may be affected by immune changes in pregnancy. Guidelines suggest consideration of nucleos/tide analogs (NA), i.e., tenofovir, (TDF) in highly viremic mothers to reduce vertical transmission risk. HBV variability affects CHB outcome, but little is known about HBV genetic changes in pregnancy due to immune or NA selection.

To evaluate HBV diversity in NA treated or untreated pregnant vs. post-partum CHB carriers.

In plasma collected from 21 mothers (7 matching pre/post-partum), HBV serological tests, genotype and viral load were assayed. The HBV pre-surface (S) /S overlapping polymerase (P) (N = 20), pre-core (C) /C (N = 11) and/or full genome PCR amplicons (N = 3) underwent clonal sequence analysis.

The median age was 31 y, 71% Asian, 68% genotype B or C, 33% HBV eAg+, 5 received TDF (median HBV DNA 8.5 log IU/ml). In untreated mothers, median antepartum vs. post-partum ALT was 21 vs. 24 U/L and HBV DNA was 2.7 vs. 2.4 log(10) IU/ml. ALT and/or HBV DNA flares occurred during pregnant and/or post-partum period in 47% (10/21). Clonal sequencing antepartum showed the presence of minor “a determinant” and/or vaccine escape mutants (VEM) but drug resistant variants were infrequent. Analysis of pregnant vs. post-partum samples showed different HBV variants and viral diversity.

Differences in immune and/or by NA selective pressures during pregnancy may affect HBV evolution during pregnancy. The presence of minor VEM warrant infant follow-up.

Below:  Neighbor-joining phylogenetic reconstruction of the HBV pre-S/S (A, N = 20), Pre-C/C (B, N = 11) and full genome (C, N = 3) using the bootstrap method

Below: Comparison of distance amongst HBV quasispecies in patients during pregnancy and post-partum in pre-S/S (A, N = 5) and pre-C/C (B, N = 5) region. Measurement of distance within patient samples is shown and compared to measurement of distance within patient samples categorized by genotype. A comparison of relative evolutionary distances of patient samples collected at different time points is shown

Full article at: http://goo.gl/RQVGvW

By:

Boris Virine, Shan Gao, Tong Wang, Samuel S. Lee, Carla S. Coffin

Liver Unit, Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

Boris Virine, Shan Gao, Guido van Marle, Carla S. Coffin

Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, 3280 Hospital Drive NW, University of Calgary, Calgary, AB, Canada

Carla Osiowy

Bloodborne Pathogens and Hepatitis Laboratory of the National Microbiology Laboratory, Winnipeg, MB, Canada

Shan Gao

Artifical Liver Centre, Beijing YouAn Hospital, Capital Medical University, Beijing, China

Eliana Castillo

Maternal Disorders in Pregnancy, Section of Internal Medicine, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

Steven R. Martin

Department of Pediatrics, Alberta Children’s Hospital, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

Kimberley Simmonds

Alberta Health, Government of Alberta, Edmonton, AB, Canada

   

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Translating PrEP Effectiveness into Public Health Impact: Key Considerations for Decision-Makers on Cost-Effectiveness, Price, Regulatory Issues, Distributive Justice and Advocacy for Access

Read at: http://ht.ly/Q6ptI HT @UvA_Amsterdam 

Discussion

In considering the role that PrEP can play in combination prevention programmes, decision-makers must determine who can benefit most from PrEP, how PrEP can be provided safely and efficiently, and what kind of health system support will ensure successful implementation. To do this, they need contextualized information on disease burden by population, analyses of how PrEP services might best be delivered, and projections of the human resource and infrastructure requirements for each potential delivery model. There are cost considerations, varying cost-effectiveness results and regulatory challenges. The principles of ethics can inform thorny discussions about who should be prioritized for oral PrEP and how best to introduce it fairly. We describe the cost-effectiveness of PrEP in different populations at higher risk of HIV exposure, its price in low- and middle-income countries, and the current regulatory situation. We explore the principles of ethics that can inform resource allocation decision-making about PrEP anchored in distributive justice, at a time when universal access to antiretroviral treatment remains to be assured. We then highlight the role of advocacy in moving the PrEP agenda forward.

Conclusions

The time is ripe now for decisions about whether, how and for whom PrEP should be introduced into a country's HIV response. It has the potential to contribute significantly to high impact HIV prevention if it is tailored to those who can most benefit from it and if current regulatory and pricing barriers can be overcome. Advocacy at all levels can help inform decision-making and push the access agenda to avert HIV infections among those at highest risk of HIV exposure. The benefits will accrue beyond the individual level to slow HIV transmission at the population level.

Below: Regulatory approval in trial host countries for daily TFD/FTC