ASHM Report Back

Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.

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John Brooks from the CDC in Atlanta provided an update on the HIV outbreak first identified in Indiana in December 2014. I reported on his first update from the IAS Conference in Vancouver in July last year.

A couple of things are very noteworthy from these presentations. The response to the outbreak was dramatic, all be it very costly, and effective. What is hugely upsetting is that it could have been prevented with a good public health approach to HIV in the first instance.

A small cluster of HIV infections were identified in a rural county in Indiana. Case follow-up and contact tracing has identified 188 infections. The vast majority of these were identified in the first half of last year with only 11 being identified more recently, and of those the majority had been approached but declined testing previously.

A lot of features made this a perfect storm: no needle and syringe program; high levels of injecting (4 - 15 times daily and sharing with 1 - 6 partners) the reason for this is that the main drug injected was oxymorphone, which sells on the street for up to $140 per tablet, so people inject small doses, regularly to manage withdrawal. High levels of intergenerational sharing, with the belief that this was protective.

The county has the lowest socio-economic profile. Access to health care was limited, many people were uninsured and not registered for social security, unlicensed, not working and did not have common documents such as birth certificates.

This is an excellent presentation which show how a significant epidemic can occur in close knit community with limited access to resources, education and information. Viral sequencing has demonstrated that these were very recent infections and all linked. 

The plenary

http://www.croiwebcasts.org/console/player/29695?mediaType=podiumVideo&

and all of the slides amd MP3 are available at http://www.croiwebcasts.org/y/2016/25?link=nav&linkc=date

There was an HCV positive rate of >90%. But the HCV, unlike the HIV was well established in the cohort, coming from multiple sources over many years. A complementary presentation by Sumathi Ramachandran, Networks of HCV Transmissions Among Persons Who Inject Drugs: Indiana, 2015  looks at hepattiis C infection in this community can be found at http://www.croiwebcasts.org/console/player/29742?mediaType=slideVideo& 

There has been considerable discussion about the potential for outbreaks in rural and remote communities in Australia. This experience is one which should be viewed by all involved in the public health response to HIV and by all those involved in policy making which impacts public health.

 
CROI 2016: Intensive cervical cancer screening only needed in HIV positive women with low CD4

Intensive cervical cancer screening may be appropriate for HIV-positive women with a CD4 count below 500 and for immunosuppressed solid organ transplant recipients--but not for HIV-positive women with more CD4s or for women on immunosuppressive therapy [1]. Those conclusions arose from a 121,000-woman case-control study in the Kaiser Permanente healthcare system in northern California. Women with HIV had twice higher odds of advanced cervical intraepithelial neoplasia (CIN) or cervical cancer than women without HIV.

 

Kaiser investigators conducted this study to get a better fix on which HIV-positive and other immunosuppressed women need intensive cervical cancer screening. The researchers considered all women 18 to 70 years old in care between July 1996 and June 2014. Cases were women with incident (newly diagnosed) CIN 2, CIN3, or cervical cancer, designated CIN2+ or CIN3+. For every case the researchers identified 5 women without CIN2+ matched by age, diagnosis date of the case, years in the Kaiser system, and date of first Kaiser Pap test. They analyzed risk of CIN2+, CIN3+, and cancer in (1) all HIV-positive (versus negative) women, (2) HIV-positive (versus negative) women grouped by recent CD4 count below 200, 200 to 499, and 500 or higher, and (3) women with non-HIV immunosuppression, including immunosuppressive therapy (such as calcineurin inhibitors and corticosteroids) in the last 18 months (versus no therapy) and solid-organ transplant (versus no transplant).

Cases were 20,146 women with CIN2+, including 11,275 with CIN3+ and 646 with cervical cancer. Because of matching, cases and controls had the same average age (36) and similar numbers of years in the Kaiser system (6.4 and 6.6 years). Cases and controls were also similar in proportions of whites (54% and 49%), Hispanics (20% and 21%), and blacks (8% and 9%). Cases included a higher proportion of smokers (19% versus 13%). About 2% in each group had been vaccinated against HPV.

Cases included 36 women with HIV (0.18% of 20,146) and controls included 79 HIV-positive women (0.08% of 100,780). All of this percentage difference lay among women with a CD4 count below 500. The proportion of HIV-positive cases with a recent CD4 count above 500 was 0.04%, exactly the same proportion of HIV-positive controls with a recent CD4 count above 500. Numbers of cases and controls with recent immunosuppressive therapy were 1370 (6.8% of cases) and 6429 (6.4% of controls). Cases included 51 transplant recipients (0.25% of cases) and controls included 69 transplant recipients (0.07% of controls). 

In adjusted analyses, compared with HIV-negative women, HIV-positive women had 2.0-fold higher odds of CIN2+ and 2.3-fold higher odds of CIN3+. HIV-positive women with a recent CD4 count under 200 CD4s had 5.7-fold higher odds of CIN2+ and women with 200 to 499 CD4s had 3.0-fold higher odds. But risk of CIN2+ was not greater in HIV-positive women with 500 or more CD4s compared with HIV-negative women. The same held true for the CIN3+ analysis: Odds were 5.4-fold higher with a recent CD4 count under 200 CD4s and 3.6-fold higher with 200 to 499 CD4s, but risk was no greater in women with 500 or more CD4s.

Women with a solid-organ transplant had independently higher odds of CIN2+ (3.3-fold) and CIN3+ (2.9-fold). But women on immunosuppressive therapy did not have higher odds of CIN2+ or CIN3+. 

Among the 646 women in whom cancer developed, 2 (0.3%) had HIV compared with 0 of 3230 matched controls; 34 of 646 women with cancer (5.3%) had recent immunosuppressive therapy compared with 156 of the 3230 matched controls (4.8%); and no woman with cancer had a solid-organ transplant compared with 4 matched controls (0.1%). 

The Kaiser team concluded that HIV-positive women had 2-fold higher odds of CIN2+ and CIN3+, but these higher odds applied only to women with a recent CD4 count below 500. Solid-organ transplantation conferred 3-fold higher odds of CIN2+ and CIN3+, but recent immunosuppressive therapy did not affect CIN2+ risk. 

Take home message: more frequent cervical cancer screening may be needed only for subsets of women with HIV and non-HIV immunosuppression, including HIV-positive women with a CD4 count below 500 and solid-organ transplant recipients. They suggested that future studies addressing these issues "should take into account harms and costs anticipated with various screening strategies."

Reference

 

1. Silverberg MJ, Leyden W, Steven Gregorich S, et al. Is intensive cervical cancer screening justified in immunosuppressed women? Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 162.

Tagged in: CROI2016
CROI 2016 : Single Dose Zoledronic Acid Prevents Antiretroviral-Induced Bone Loss : Proof of concept study

HIV infection is an independent risk factor for osteoporosis. Initiation of ART induces additional 1-6% loss in bone mineral density (BMD). ART-associated bone loss occurs early and happens with most of ART agents.

Zoledronic acid is a biphosphonate drug licensed for the treatment of bone-related cancers alongside chemotherapy and for the treatment of osteoporosis in men and women at increased risk of fracture. It is administered as an infusion once a year. The drug slows down the loss of calcium from the bones, reducing the risk of fractures.

Reduced bone mineral density is common in people living with HIV, and as previously noted, modest bone mineral loss is a common occurrence during the first year of antiretroviral therapy. Investigators from Emory University School of Medicine, Atlanta, designed a study to investigate whether a single infusion of zoledronic acid could limit bone mineral loss during the first year of antiretroviral therapy.

This was a single-centre, randomised, double-blind, placebo controlled phase 2 study. Patients starting HIV therapy for the first time with no history of bone loss were eligible for inclusion. All participants received an antiretroviral regime of atazanavir with tenofovir/emtricitabine. Patients were randomised to receive a single 5mg infusion of zoledronic acid or placebo. The study lasted 48 weeks with assessment of bone turnover and bone mineral density at baseline and weeks 12, 24 and 48.

Therapy with zoledronic acid was associated with a 74% reduction in bone loss by week 12. The benefits persisted through to week 24 and 48 (65% and 56% reduction, respectively, relative to placebo).

By week 12, patients in the treatment arm had an 8% increase in lumbar spine bone mineral density relative to placebo, the difference increasing to 11% at weeks 24 and 48. At week 48, lumbar spine bone mineral density had increased by 2% in patients treated with zoledronic acid; this compared to a 4% decrease among patients who received the placebo. Lumbar spine T- and Z-scores were significantly higher among patients who received zoledronic acid versus placebo at all follow-up points (all p < 0.05). Similar trends were also observed at the hip and femoral neck.

Zoledronic acid was well tolerated with no major adverse events reported. Rates of viral suppression and CD4 cell increase were similar between the treatment and placebo arms.

The investigators conclude that a single infusion of zoledronic acid at the time HIV therapy was started prevented antiretroviral-induced bone resorption and bone loss at key fracture-prone body sites. The benefits of therapy were present at week 12 and persisted through 48-weeks of follow-up. The researchers suggest that zoledronic acid could be used as a prophylaxis against bone mineral loss during the first year of antiretroviral treatment and call for a multicentre randomised trial to confirm their findings.

Take home message: Single dose of zoledronic acid infusion may be an effective preventative measure of BMD loss in HIV

Tagged in: CROI2016

Five of 404 men who have sex with men (MSM) or transgender women taking a maraviroc-containing preexposure prophylaxis (PrEP) regimen or tenofovir/emtricitabine (TDF/FTC) picked up HIV infection in the 48-week HPTN 069/ACTG A5305 trial [1]. All infected men had no, low, or variable drug levels at HIV seroconversion. But results of a substudy suggested maraviroc alone may be less potent than maraviroc/TDF or maraviroc/FTC [2]. 
 
Maraviroc is a reasonable PrEP candidate because it concentrates in the genital tract and rectum and can be taken once daily. To explore maraviroc's potential as PrEP alone or with TDF or FTC, HPTN and ACTG collaborators recruited HIV-negative men or transgender women who did not inject drugs and who had condom-free anal sex with one or more HIV-positive or serostatus-unknown men in the past 90 days. The researchers randomized them to 48 weeks of maraviroc alone, maraviroc/FTC, maraviroc/TDF, or TDF/FTC, all once daily. Thus each man took 3 pills daily (including matching placebo).
 
The trial enrolled 406 people, all male at birth and 7 (2%) transgender women. Median age stood at 30 years and ranged from 18 to 70. Of the 406 people randomized, 404 started study drugs and 340 (84%) completed the study. Thirty-seven participants (9%) stopped study drugs early, with no differences by study arm. Time to permanent drug discontinuation did not differ between arms. Analysis of 18 men per study arm showed that TDF or FTC did not affect maraviroc concentrations. In a random subset of 160 participants, all drugs could be detected in 83% of participants at week 24 and 77% at week 48, with no difference between arms.
 
Ninety men (22%) had 115 sexually transmitted infections diagnosed during follow-up, a finding indicating a high rate of continuing sex. Five men became infected during follow-up for an annual incidence of 1.4% (95% confidence interval 0.8% to 2.3%). Four were taking maraviroc alone and one was taking maraviroc/TDF.(The study was not powered to evaluate efficacy.)
 
At HIV seroconversion, the man taking maraviroc/TDF had undetectable levels of both drugs. One man on maraviroc alone had no detectable maraviroc at seroconversion, while the other three had levels of 0.7, 6.7, and 145 ng/mL. The expected predose maraviroc level is 32 ng/mL, so only one man had good maraviroc levels at seroconversion. But in all 3 men with detectable maraviroc at seroconversion, levels were highly variable throughout the study, indicating off-and-on PrEP use. All 5 men got infected with virus using the R5 receptor (which maraviroc blocks) and none had genotypic resistance to maraviroc.
 
The HPTN/ACTG team proposed that "maraviroc-containing regimens should be considered for testing in clinical efficacy trials." Whether to go ahead with solo maraviroc or maraviroc plus TDF remains an open question. A substudy in which researchers tested the four regimens in colorectal tissue explants of 55 study participants found significantly less viral suppression with maraviroc alone than with the three combination regimens [2]. But the HPTN/ACTG team noted that they have yet to correlate those results with pharmacokinetic adherence data. Also, the same regimens are being tested in women, so decisions on future trials must await those results.

Take home message: Maraviroc is a promising alternative oral HIV PrEP agent but research is still at very early stages.


References
1. Gulick R, Wilkin TJ, Chen Y, et al. HPTN 069/ACTG 5305: phase II study of maraviroc-based regimens for HIV PrEP in MSM. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 103

2. McGowan I, Nikiforov A, Young A, et al. PrEP impact on T-cell activation and explant infection: HPTN 069/ACTG 5305 substudy. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 104. 

Tagged in: CROI2016
Amazing PrEP Technology

Just a short not re PrEP implant - Poster 879

Looks like a implanon - looks easy to insert and to remove - Initially seems to deliver effective drug concentrations for 3 months - but surely this will improve.

" developed a biodegradable TFPD for subcutaneous delivery of TAF for HIV PrEP. The size, shape, and release rate of the device are tunable over a >8-fold range"

Fantastic - surely multiple compounds could be delivered this way

Surely a device that lasts for 12 months or would be perfect for PrEP.

Tagged in: CROI2016
Vaginal Rings - Empowering Protection?

The Dapivirine vaginal ring empowers women by giving them a device that they can use to protect themselves from HIV infection and which in no way requires agreement or permission from their male partner/s. Two landmark studies were presented at CROI. Adherence had always been the problem seen in previous studies of similar technologies.

MTN 020/ Aspire Study

This was a placebo controlled RTC. 2629  <50% married women from 4 African countries were randomised to two arms - one was the Dapivirine containing ring the other was a placebo ring. Dapivirine is an nnrti. The median age of the women was 26 - ranging from 18 to 45. The ring is replaced every four weeks and meant to be in situ all of the time.

Adherence was assessed by measuring blood levels - levels >95 pg/ml was consistent with > 8 hrs of use. 82% of plasma samples were at this level or greater. Adherence would be over estimated if the ring was inserted > 8 hrs prior to the clinic visit. Returned rings were also assessed for residual drug. 84% were found t have levels < 23.5 suggesting adequate compliance.

median followup was 1.6 years. Women attended 91% of expected visits.

Overall there was a 37% reduction in expected HIV infections in the women on the active treatment arm. Interestingly in women <21 years of there was NO reduction in infections and in women above 21 years there was a 51% reduction in expected infections. Analysis suggested poor adherence in women < 21 yrs of age.

The rings were well tolerated in both arms with essentially no significant adverse events.

 

The Ring Study  IPM 027

This was an RCT double blinded trial studying the safety and efficacy of a Dapivirine vaginal ring. 1959 women from two African countries were randomised 2:1 Dapivirine ring and placebo. The women aged 18 - 45 received HIv prevention counselling. Adherence was objectively assessed by plasma levels throughout the trial and measurement of residual drug in returned rings. Rings were replaced every 4 weeks. The study concluded end 2015 after most women had been tudied for two years. All women will be offered an active ring at the first visit after conclusion of the study.

Expected HIV infections were reduced by 31% in the group using the active ring.

The study organisers concluded that the ring was safe and well tolerated with an overall reduction of 31%. They noted that was a high incidence of HIV infection in the group studied of 8 % per year.

 

These number do not sound that great to me. However they do compare pretty well to the IPPREX findings presented in 2011 re oral Truvada as PrEP.  It may be that adherence would be much better in an open label situation with better levels of education and understanding about the importance of always having the ring in situ no matter what else is happening. So that as we see in community settings adherence is much better and the protection against infection almost absolute.

Tagged in: CROI2016
STI screening in the context of PrEP

Wednesday 23rd Feb Session TD-12

It’s Complicated: Renal Function and STIs in PrEP Users.

STI Data From Community-Based PrEP: Implementation Suggest Changes to CDC Guidelines.

Presenter: Sarit A Golub (NY, USA). Oral abstract an Poster.

 

Main findings of a review of STI screening in the context of PrEP;

Current CDC guidelines recommend screening at 6/12 intervals or earlier only if symptomatic.

They decided to screen all PrEP attendees routinely regardless of symptoms at 3/12 intervals.

They found that 77% of STIs would have been missed if they weren’t screened at the 3/12 routinely because of reporting as asymptomatic.

STIs screened were; Gc, CT, RPR in urethral and rectal samples. Pharyngeal testing was also done but not included in this study. The majority of PrEP attendees were between 22-40yrs of age.

Test of cure was only conducted on those that were documented as not having received first line therapy at the time of initial diagnosis. Current treatment for rectal CT was 1g Azithromycin, but 7 days Doxycycline was offered if TOC was +ve.

The researchers have also proposed a theory for why there was a spike in STI detection at 6/12. Anecdotal only, but PrEP attendees reported increased sexual risk activities after the 3 month initial HIV screen had come back negative, so they could actually believe that PrEP was effective for them.

Overall they are recommending that in light of many new PrEP guidelines and protocols being developed that STI screening of MSM on PrEP should be 3/12 regardless of symptoms.

 

These recommendations are in fact consistent with our current STIGMA guidelines for MSM screening that suggest testing up to 4 times per year.

http://stipu.nsw.gov.au/wp-content/uploads/STIGMA_Testing_Guidelines_Final_v5.pdf

Something additional to consider is that should and if PrEP be prescribed by any clinician, without S100 authority, then there may be a need for some re-education into promoting sexual health screening especially in the community general practice setting. 

Tagged in: CROI2016 PREP STI
With or without ART, CVD risk matters

Session 0-4 Complications from Head to Toe

Early Antiretroviral Therapy Does Not Improve Vascular Function: A START Substudy. Abstract 41

Presenter: Jason V. Baker (Minneapolis, MN, USA)

They utilised diastolic aspect of cardiac BP waveforms to assess elasticity and vessel function.

Participants were generally a young cohort in their 30s and with CD4 counts >600

CVD (Cardio-vascualr disease) risk was low for the study cohort that was on ARVs, but was slightly increased for those participants that were in the ARV deferred group.

For HIV +ve patients consistent changes were noted across all age groups. 

It was notable that both HIV +ve groups (Those on ARVs and those in deferred arm) had lower elasticity baseline in comparison to the general (non-HIV) population, from CARDIA.

No specific difference in elasticity between ARV and deferred HIV +ve groups.

Overall the findings of the substudy did not show any benefit on vascular elasticity from commencing ART early. It did however highlight how vascularity is compromised within HIV +ve patients and hence for all our HIV +ve patients regardless of age we should take assessment of their CVD risk seriously and conduct this routinely, even for the young of age and those with suppressed viral loads and good CD4 counts. 

Tagged in: CROI2016
PrEP - new alternatives to tenofovir / ftc"

Alternative PrEP Regimen

Maraviroc + FTC may be the first alternative PrEP regimen to become available. Obviously this is great for people who for some reason cant take or tolerate TDF/FTC.

Roy Gulick presented 48 week data from HPTN 069 - a RCT   double blinded safety and tolerability trial comparing four treatments arms

      Maraviroc alone

      maraviroc + FTC

     maraviroc + TDF

     Tenofovir DF + FTC

THIS WAS NOT A TRIAL OF EFFICACY

406 HIV-ve MSM older than 18 years deemed to be at some risk for acquiring HIV ( needed to have a self reported history of unprotected anal intercourse with either a known HIV+ve man or a man of unknown HIV sero-status within the previous 90 days.) were randomised to one of the four arms and followed up for 48 weeks. 28% were black, 22% latino. eGFR at enrolment needed to be > 70.

Maraviroc was studied because it was an available ARV, it was already known to be concentrated in rectal tissue, and it was known to be well tolerated.

Findings - All arms were well tolerated - no significant safety or tolerability differences were found. There were 5 seroconvresions in the study- 2 of these had no detectable drug; the other three had detectable drug and these were all in the maraviroc alone arm. But this study was not set up to look at efficacy.

 

Injectable Cabotegravir - PrEP Study in Monkeys but with Intravenous challenge.

Could Cabotegravir LA protect against IV transmission of HIV?  Long acting Depot CAB injection would suit IV drug users but would it work?

Three arms  injected with CAB LA with varying doses at week 0 and week four. one group received only one dose at week 0.  IV challenge given at week 2.    8 macaques in each group     Five macaques remained untreated as controls.

All 5 macaques were found to be infected one week after challenge

two 50mg doses given at week 0 and 4weeks resulted in 7 out of 8 macaques remaining uninfected

one 50mg dose at week 0 resulted in all 8 macaques in that group remaining uninfected

one 25mg dose at week0 plus one 50mg dose at week 4 resulted in 6 out of 8 macaques remaining uninfected

Notwithstanding the difficult to explain single infection in the first group these results suggest that adequate dosing with CAB LA will protect IVDU's from IV infection with HIV. Fwurther study ill be done.

ECLAIR - Long acting Injectable PrEP   Safety and PK study

This would be great for a subsection of our patients at some stages in their lives.

Phase 2a randomised trial of Cabotegravir LA - INSTI . Doses based on Phase 1 data, supported by animal studies. 127 patients randomised receive injections given at 3 monthly intervals of CAB LA or saline.

There was a 4 week induction period of oral therapy. Safety tolerability and PK was assessed through the trial until the 41 week endpoint.

Avaerage age 30. 57% white

Both oral and LA doses were well tolerated. Absorption rates were faster than expected higher peaks and lower troughs with 21% falling below the IC90. Most significant AE's were injection site reactions in the active treatment arms. There weren't many problems with the saline injections. ISR's lasted 5 days on average. There were two seeroconversions - one receiving saline, the other occurring in the followup phase of the CAB LA group. The dose is being reviewed in light of the PK data.

 

Topical Rectal microbiocide - MTN 017

Phase 2 three period randomised sequence open label safety acceptability

comparing rectally applied reduced glycerine 1% tenofovir with oral TDF/FTC

in each 8 week study period 195  MSM > 18yrs with a history of being ano-receptive either used the topical rectal gel daily; used the rectal gel before and after anoreceptive sex; or took TDF/FTC orally. Participant switched method every 8 weeks with a "washout " period of one week between each change.

Subjects were given lots of support to be adherent - eg daily texts to ensure daily use of the rectal gel . Very frequent interviews and questionairres. Adherence was objectively by collecting blood, rectal fluid and rectal tissue samples. Adherence was found to consistent with >80% of expected doses taken/used.

138 were screened "out" because of the presence at enrolment of STI's or HIV infection

There were few AE's. All methods were well tolerated. All methods were "liked" by the participants. There was found to be high levels of adherence in all arms. Further studies will now be done.

 

Tagged in: CROI2016

It’s amazing how far we have come in the potential of neutralizing monoclonal antibodies against HIV. John Mascola from the Vaccine Research Centre gave a great plenary on “Harnessing antibodies for HIV prevention and treatment.”

Antibodies have been used in infectious diseases for passive immunization eg RSV, zoster, hepatitis B.

Many potent broadly neutralizing antibodies have been discovered in HIV since 2009, which can bind to various sites on HIV gp41 and block viral entry into cells. These newly discovered antibodies are 500x more potent than previously and more are being found.

Studies in monkeys have demonstrated that passive immunization with these newer antibodies such as VRC01 can prevent SHIV infection.

There are early phase studies in humans. The treatment appears safe and well tolerated. Protective levels of antibodies remain in circulation for 2 months – this period can be extended by creating mutations in the Fc region that increase the antibody affinity.

Can antibodies protect against infection in humans? How much is required (as more potent antibodies are discovered, they will require lower doses and last longer, thus reducing cost. Lower dosage also means they can be administered subcutaneously rather than IV). There also needs a greater understanding of how and where exactly these antibodies work in the body.

A large scale HIV prevention study is planned using broadly neutralizing antibodies to provide antibody mediated protection in 2400 MSM in North and South America and 15000 women in Africa.  The goal – safe effective administration sc every 4/12 for PrEP.

There needs to be protection against wide variety of HIV strains – combining antibodies acting at different sites will achieve this.

Other potential roles for these neutralizing antibodies include preventing mother to child transmission intrapartum and with breast feeding – animal models show this is viable.

Neutralizing antibodies may also have a role in treating HIV infection – either alone, or complementary to ART. They may be able to reduce viraemia in primary infection, or in those with chronic infection, to treat HIV, and to assist in killing of infected cells by marshalling immune response.

So while there is work to do in translating this knowledge into viable HIV prevention and treatment options, there has been major progress in this area. Watch this space.

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Tagged in: CROI2016
Key Antiviral Therapy RCT's Cabotegravir LA injection and TAF(again)

GS - US- 311-1089   Switching Tenofovir DF to Tenofovir Alafenamide in virally suppressed patients

48 week data was presented; RCT, double blinded  evaluated safety and efficacy of switching from F/TDF to F/TAF  vs continuing F/TDF while remaining on the third agent. 50% of third agent was a boosted PI.  663 patients were randomised to the two arms. Patients vl were < 50 copies and stable. eGFR was > or= to 50

Very little failure described. The nature of the third agent made no difference to outcomes. Very foew AE's leading to discontinuation occurred.

eGFR improved and proteinuria decreased when switched to F/TAF.    BMD did not worsen in the F/TDF group. BMD improved in the F/TAF group at both 24 and 48 weeks. Lipids increased in the F/TAF group.  F/TAF was shown to be not inferior in terms of virological suppression.

 

Latte 2  week 32 results - Cabotegravir + Rilpilvirine as long acting maintainence therapy,  INSTI and NNRTI long acting injectable nano-suspension. 

Phase 2b open label study ART naïve. 20 week induction daily oral CAB + ABC/3TC randomised to one of three arms - IM CAB LA + IM RPV LA every 4 weeks ; or the same every 8 weeks ; or to remain on the oral CAB + ABC/3TC

309 subjects enrolled.  median age 35.  8% female.  15% African American  Median CD4 ^400  19% viral load > 100,000.

32 week data. 286 subjects randomised to maintainence therapy. most common AE was injection site pain with 99 of these reported as mild. These lasted a median of 3 days with all resolved by 7 days. 1% eventually withdrew citing injection site reaction. most non ISR AE's were fever, fatigue , and flulike symptoms. There was one death unrelated to study due to epileptic eizure.  > 95% cited high level of satisfaction with the injectable therapy.

All arms demonstrated comparable antiviral activity. At this time no regimen has been ruled out.

 

 

 

 

Tagged in: CROI2016
Plenary 2 - Joe Eron - Where we are and where we are going

Tuesday plenary 2 - A great overview of the current situation and where we are headed

90 90 90 are high targets

Integrases will help achieve these higher proportion of fully suppressed patients for longer before resistance occurs and needing fewer regimen changes over the projected treatment period for some of 80 years.

Hurdles include

     -persisting treatment gap - those in care and not in therapy > 10 % in most clinic populations

     -whole life treatment from diagnosis despite

          -adverse events, pregnancy, childhood and adolescence, periods of poor adherence, drug interactions

     -Toxicity - but this is decreasing

              eg TDF will be replaced by TAF - lessening BMD loss and reducing proximal renal tubule issues

                   Duel therapies - eg Dolutegravir + 3TC - less exposureto potential toxicities

     - Resistance - but the use of potent therapies up front has made resistance rare

     - Are there enough agents to last 80 years

            New agents/ different classes will overcome resistance to previously used drugs

                         Dolutegravir

                         TAF

                         Doravirine

                         Maturation inhibitors

                         Attachment inhibitors

                         Monoclonal antibodies

     - Adherence issues - particularly at some stages in their life for some patients - adolescents and drug                   users for example - Long acting therapies like Cabotegravir and Rilpilvirine will help

               Drug implants

               Vector delivery

Tagged in: CROI2016

A brief blog reviewing the Bernard Fields Lecture. Monday 22nd Feb.

T Cells Control of HIV: Implications for Vaccines and Cure.

Speaker: Dr Bruce D Walker (Harvard, MA, USA)

In summary CD8 T cell immunity is still undergoing vital research in assessing how it impacts on overall immunity specifically relating to HIV. Can it help us in a cure or vaccine development? 

Known that CD8 T Cells can kill infected cells before progeny virions are produced. Yang 1997 showed that In vitro CD8 cells can kill HIV infected cells.

In order to assess T Cell response in initial pre peak viremia infection they are studying HIV infected babies in Durban, South Africa. FRESH program was implemented. It was noted within these patients that the rate of increase in viral load was similar across all new infection babies, but the actual peak viral load number and time to reach that in an individual varied. http://ragoninstitute.org/international/fresh/

 From current findings they have found that CD8 cells increase their activity within the human body just after initial exposure to HIV, a substance known as PD-1 is expressed and the more of this that is expressed over time there appears to be some correlation with the immune system getting turned down in regards to response. This was apparently similar to what has been noticed with cancer modulating cells and immune response impact.

They have been able to show that HIV some how activates CD8 activity –they hypothesize that perhaps active CD8 T cells are HIV specific. It was noted that an increased level of CD8 cell activated initial stages of infection was linked with a lower viral load set point.

Two other markers noted to be of relevant were, BCL-2 and perforin. As BCL-2 was activated CD8 cells underwent increased apoptosis, and similarly as there was a loss in perforin there was a progressive decline in CD8 functionality.

Overall early treatment does impact the overall quality of the immune response. To further hypothesis but if CD8 cell functions were maintained by commencing treatment in the pre-viremia stages of infection exposure could this help in the development of a cure and it’s effectiveness.

At the conclusion of the talk, despite being moderately confused with the biochem aspects, I got the impression that for now in order to help the development of future effectiveness of a potential cure we need to maintain baseline immunity of newly diagnosed HIV positive patients as much as possible, and prevent the exhaustion or destruction of CD8 cells after peak viremia.

I’m not sure if I would use this particular pitch to promote early commencement of ARVs in patients or for increased testing programs to detect earlier, but it’s food for thought as to why there is a possible other reason to suppress viral loads as early as possible.

 

Plenary 1 - Overview of Monoclonal Antibodies

The use of Monoclonal antibodies in HIV therapy seems to be close at hand. The first plenary of the conference focussed on this.

First potential compound identified in 2009 - today there are over 500 individual isolates. Initially investigated to better understand pathways to effective vaccination there seem to be clear applications for use in preventing HIV infection (PrEP) as well as suppressing viral replication.

Two attributes of MA are of interest

                - Potency - dose required to neutralise the majority of viruses, and

                 -Breadth - the % of different HIV "strains" neutralised.

Currently no human data regarding passive protection from infection with monoclonal antibodies. Within a short time should have antibodies that bind four different sites.  There is PK data and safety data from phase 1 trials. Animal data shows effectiveness.

The first trial in humans to assess the protectivity of MA will begin later in 2016.   Based on earlier studies this will be a placebo controlled trial in high risk males in North America and high risk females in Africa.

It is likely that future compounds will be more potent and it is also likely that multiple compounds will need to be used at once to provide greater breadth.

There are a number of areas where monoclonal antibodies would have application clinically.

         -Acute HIV infection  to prevent or limit seeding of viral reservoirs

         -to maintain long term viral suppression  - given by injection every two -three months  

         - to reduce cell associated reservoirs.

Advantages of proposed compounds are

         - they are distinctly different current medications and their resistance profiles will be different

         - they have the potential to eliminate infected cells and may have a role in eradication

Limitations include

         - they are unlicensed biologicals

         - single compounds do not cover %100 of virus

In any case these exciting developments seem to indicate that we will have effective new tools within a relatively short time frame that will be effective at preventing infection as well as maintaining viral suppression. They may also have a role in assisting with eradication of the HIV infected cells.

 

 

Tagged in: CROI2016

This paper reviewed the increase in viral suppression and sustained viral suppression in USA adults on ART between 2009 and 2013.

Viral suppression increased in a linear fashion from 72 - 80% a significant 2% rise year on year. Sustained virological response followed a similar trajectory from 58% - 68% over the same time. This was not explained simply by an increase in number of people on therapy.

Women, 18-29 year old's, 30-39 year old's, African Americans all had a greater benefit than the overall. MSM were higher than the average at all time points.  There were two Guidelines introduced during the study period which actively promoted treatment and barriers and delays to accessing AIDS drugs. All suggesting that policy change is having impacts.

This is Oral paper number 53, in session O-5, if you want to have a look when the presentations go on-line. http://www.croiconference.org/

Sydney Rosen presented this SA randomised trial. Patients in South Africa were randomised to start ART on first visit or delay to standard guidelines (which require CD4 testing and behavioural visits, which can take up to 4-6 visits). Three quarters in the RapIT arm started on the first visit (TB was the main cause for delay in the RapIT arm). The RapIT arm had improved outcomes. It saw greater effect for young people, in primary care clinics and loss to follow up was very low.

The presentations should be on line shortly http://www.croiconference.org/ this one is #28 in Session Oral-2

Recovery of Bone Mineral Density After Stopping Oral HIV PrEP

The slight loss in bone mineral density associated with HIV PrEP antiretroviral use is reversible in young adult patients who stop taking the drugs, according to findings presented by Robert Grant today at the CROI in Boston.

 
The findings result from a bone mineral density substudy of two large clinical trials, iPrEx and iPrEx OLE.Data from the substudy presented today illustrate that bone mineral density decreased a measurable but clinically insignificant amount over the course of a year in young adult males and transgender participants with an average age of 24 taking a protective amount of PrEP. However, six months after stopping the regimen, bone mineral density levels in the spines of these individuals increased to levels consistent with study participants of the same age who took a placebo. Hip bone mineral densities also increased in the first six months after stopping PrEP and returned to normal levels by a median follow-up time of 73 weeks.
 

Previous studies using sensitive scans have shown that HIV medications containing tenofovir slightly reduce bone mineral density, though not to a degree at which patients experience complications. This is the first study to show that this effect is reversible when a patient can stop PrEP, such as when an individual enters into a mutually monogamous relationship with another HIV-negative individual. 
 

Take home message: It appears that Truvada-based oral PrEP may not pose an irreversible effect on bone mineral density in young adults.

Tagged in: CROI2016

This WHO consultation followed on immediately from the CDC. This was one of the data collection workshops aimed at feeding into the development of the new WHO resistance testing guidelines. I was the only person in the audience from South East Asia and the Western Pacific. But a survey can be completed on line Insert website.

 

What was important here is the trade-off between affordable therapy for most people versus switching (and abandoning 1st line therapy). Willem Venter, from South Africa, cautioned against switching, and introduced the practicality that this would not be affordable, if 85% of people were benefiting from that therapy. Jonathan Shapiro questioned the 15% versus 85% assumption about resistance, and suggested there might need to be more consideration of this.

I raised the issue that there was no-one in the audience from ESA and the Pacific, including Australia. The consultation is open online and I was told consultation would come from the WPRO and SEPRO offices.

 

http://www.who.int/hiv/topics/drugresistance/en/ 

CROI 2016 Case-based workshop on HCV

I found the case-based workshop on HCV quite useful. The session highlighted some of the difficult therapeutic scenarios with current DAAs. It also mentioned some of the limitations of current DAAs and research gaps in this area.

Here I have summarised important points relevant to HIV & HCV prescribers. Standard abbreviations are used.

HIV and HCV co-infection

Even though efficacy of current DAAs in HIV/HCV high and generally equivalent to HCV mono-infections, this is still a "special" population with therapeutic challenges

DDI with HIV ART

LDV/SOF with TDF increases tenofovir plasma concentrations; greater effect when combined with RTV boosted PIs. Avoid LDV/SOF if CrCl< 60 or with TDF+ RTV-boosted PI

However, the clinical significance of elevated TDF level here is not very clear at this stage. But when LDV/SOF and TDF given, frequent monitoring recommended eg week 2 & 4 renal functions monitoring

What about TAF and LDV/SOF? Data was presented for E/C/F/TAF and R/F/TAF. Tenofovir concentration are increased but well below the concentrations with TDF.

Take home message: LDV/SOF and TDF:  Be aware contra-indications and frequent renal function monitoring while on DAAs

DDI with other meds

One important DDI highlighted in the case was PPIs and SOF/LDV. Chronic PPI therapy is not uncommon in PLHIV and in many cases, it is unnecessary. There is significant decrease of LDV concentrations with PPIs. The data from HCV TARGET study sub-analysis was presented. SVR 12 with SOF/LDV was reduced from 90% to 70% when PPIs are used as baseline.

Take home message:  PPIs can significantly compromised SOF/LDV efficacy. This is good opportunity to review patients on long term PPIs and cease if not absolutely necessary. One more reason to stop unnecessary long term PPIs

Can we stop HIV treatment temporarily when there are significant DDIs with HIV ART and HCV DAAs? Panel members felt with the available of new HIV ARTs, stopping HIV treatment temporarily is not acceptable and it’s recommenced to change HIV ART to a suitable regimen prior to HCV DAA treatment.

Shorter course of DAAs

In some subpopulations, SOF/LDV and SOF/DCV 8 weeks has high efficacy comparable to 12 weeks treatment.

For an example, In GT1, treatment naive, non-cirrhotic and baseline HCV VL less than 6 million IU/mL treatment can be shorted to 8 weeks of SOF/LDV.

However, data is currently not available for HIV/HCV co-infections. The panel members recommendation was until we have more data for co-infections, avoid 8 weeks treatment.

Take home message: Avoid shorter course (less than 12 week ) of SOF/LDV or SOF/DV in HIV/HCV co-infections until more clinical data available.

 

Tagged in: CROI2016
Panel Discussion on Stigma, Trauma and Stress: Considerations for HIV Research and Programs

Monday 22nd Feb

Session MD – Panel Discussion on Stigma, Trauma and Stress: Considerations for HIV Research and Programs.

Moderator: Morenike Ukpong-Folayan (Nigeria)

Diversity in panelists: Laurel Sprague, Sethembiso Mthembu and Keith Green.

 

Speaker 1

Laurel Sprague: Limits and Complexity Research on Stigma and HIV. (Milford, PA, USA)

Complex topic for discussion and opening panelist Laurel Sprague opened with Stigma, fear, and anxiety around disease is just as important as the focus on reaching undetectable viral loads.

She continued to highlight that HIV positive people surveyed actually want not disclosing ones HIV status to be decriminalised, and it is the ongoing impact of the possibility for incarceration that is continuing HIV stigma within the US.

Discussion around the Stigma Index Questionnaire within the US and globally. http://www.stigmaindex.org

 

Speaker 2

Sethembiso Mthembu: Women’s Rights and Decision Making in Hormonal Contraception. (Durban, South Africa)

Presented on how there are overriding political issues that continue to impact on the provision of care for women, different contraception is offered in northern regions to southern regions, and based on religion and race.

Increasing awareness into the effects of hormonal contraception – in particular depo provera injection has on vaginal pH levels and thus is actually increasing the risk of HIV transmission for African women, as well as an increased link with higher rates of cervical cancer.

ECHO Study is currently looking at the direct links between administration of hormonal contraception and increased rates of HIV.

http://echo-consortium.com

Current government programs push hormonal contraception onto African women with little education or communication of possible side effects, in HIV positive females, provision of ARVs is withheld until the person can prove they have had their depo provera injection

Ongoing provisions of care complications are highlighted with African women being provided with ‘contraception only’ clinics, which will not and do not address any other complex care needs of women’s health.

We can all argue how effect depo provera is as a form of contraception that is discreet, effective and economically accessible around the world. The point raised by Sethembiso is that we need to consider and understand the impact however such hormonal contraception is being pushed in Africa not as an option but with forced prescription and the impact in relation to HIV risk.

 

Speaker 3

Keith Green: Engaging Young Men of Color in Community HIV Prevention Studies. (Chicago, USA)

Emphasis on multi-disciplinary approach and peer lead and consumer inclusion into study development and implantation.

He notes a major aspect of barriers in engaging youth consumers and participants into new studies and trials is not due to just their own stigma concerns but rather also the fact that youth inherently rebels and does not like to follow set orders or rules, and is just part of their nature as humans.

Keith also highlighted that we should not be so quick at labelling and using terms as MSM to communicate with young people, in todays day and age the better options is to ask the person how they wish the be identified and then use that term.

He has raised some interesting points, but also it does seem that it is increasingly difficult to allow interactions across all politically correct and non judgmental levels without making the research less valid, or repeatable in other settings, if allowing too many broad topics, and individual approaches helps gain numbers of consumers to participate will it then also indirectly make the research less scientifically valid?

The use of facebook and twitter proved valuable to their team in engaging and maintaining participation from youth consumers. The importance of privacy and sensitivity was highlighted but most participants were very happy to communicate via social media rather than phones. In considering the youth of today, mobile numbers change frequently, however very few will ever change their facebook or their email. Putting privacy and internet safety of information aside and assuming all was protected, one would think that this approach could not only benefit in youth interactions but also for all consumer/ client groups that are often lost to follow-up, low retention of care populations and indigenous and/or remote populations within geographically diverse Australia.

Keith repeatedly emphasis the importance of health provision to always remain culturally competent and relevant. This is of course a huge challenge in any community and country around the world especially as technology and communication avenues evolve so rapidly.

 

Open Q&A - Discussion:

The open discussion highlighted some global issues on the topic and some interesting specific examples were given. To summarize the main points of the discussion;

-       HIV prevention and control act implemented in Uganda has actually increased stigma, trauma and stress with the implantation of heavy fines on HIV positive people.

-       Is incarceration as punishment actually discrimination? In South Africa women are targeting for testing drives esp in antenatal screening – however if testing positive are indirectly persecuted, hence promoting fear towards testing.

-       Is the threat of incarceration a why in which governments globally can still impose authority.

-       Fears for women was further highlighted by the following scenario: If a man rapes a women in South Africa he is charged with rape and undergoes mandatory HIV testing, if positive he is then also charged with infecting people. On the flip side, the women raped is also tested, and if she is found to be the source, then she goes from being the rape victim to potentially facing a charge for HIV transmission to the rapist!

-       Do HIV, MSM and Sex worker clinics promote health care and reduce stigma or do they promote isolation and less integration and public understanding by segregation.

-       How can we reduced the distrust between consumer populations and research communities. Is it by educating, training and giving voice in positions to consumer/ peers. Would a society then specifically place aside allocated funding and positions for consumers/ peers to enter the industry and become researchers. In the Australian context how would this be rolled out? Similar to indigenous program models and would this encounter any population bias or speculation, helping reduce stigma or increasing it?

 

Session OS  - Opening Session - Fighting AIDS with Style 

On an additional note the final speaker of the day at the opening session was a special event guest, designer Kenneth Cole, now chairman of amfAR. He has dedicated his social and influential career in the fashion industry since 1985 to helping reduce stigma by being an individual public voice. From his efforts to not live in the dark or silence and instead pushing controversial AIDs and HIV issues into the public light.  https://www.kennethcole.com/lgfg-making-aids-history.html

It is something about the concept of stigma, trauma and stress in relation to HIV in all aspects including research barriers that should be challenged by more people speaking out and making it an acceptable public topic for discussion. When society is forced to fell comfortable about what is actually going on around it and within it, it is then that ignorance and bigotry can be overcome and help reduce stigma and hence promote public health.