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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HEPATITIS C VIRUS: GONE BY 2030?

John W. Ward, CDC, Atlanta, GA, USA

Recognizing hepatitis C virus (HCV) as a major public health threat, the World Health Organization in 2016 released a strategy for global elimination by 2030 (i.e., 90% reduction in HCV transmission and 65% reduction in HCV-related mortality). The United States (US) National Academies of Sciences has deemed US elimination of HCV a feasible goal.

HCV-Infected persons born during 1945-1965 are at greatest risk for HCV-related mortality. Certain strategies improve the HCV testing, care, and cure cascade and can reduce HCV-associated deaths. Provider education and adoption of clinical decision tools improve rates of HCV testing. Training and support of primary-care clinicians expand the workforce offering HCV services. Diagnosis of current HCV infection is improved by reflex testing of anti-HCV+ specimens for HCV RNA. Patient navigation services help persons begin and remain in care. At national and health-system levels, implementing policies and setting and measuring performance targets can improve quality of services. Issues with provider reimbursement for HCV treatment limit the number of persons treated through the Affordable Care Act and proposed changes might impact access to care. Creative solutions are needed for universal access to HCV treatment. Reducing US HCV transmission rate by 90% requires a targeted approach. Incidence is rising among persons who inject drugs (PWID); an increasing number of infants are born to HCV-infected mothers. Harm reduction services (e.g., clean injection equipment, drug treatment services) can prevent >70% of infections among PWID; HCV testing and treatment can enhance prevention. Access to these interventions is poor, particularly in areas with high HCV incidence. In the absence of an effective HCV vaccine, reaching elimination goals for transmission will require improved detection and investigation of transmission networks, increased availability of harm reduction services, affordable HCV therapies, and better evidence and capacity to deliver prevention services. Targeted intervention delivery to incarcerated and other vulnerable and marginalized populations is key to achieving elimination goals. With strong societal commitment and support for implementing comprehensive HCV prevention, testing, care, and treatment, HCV can be eliminated as a public health threat in the US.

Tagged in: CROI 2017

Comment: Abstract follows.

Modelling studies presented at CROI in 2016 predicted that prompt treatment of Hepatitis C with direct acting antivirals (DAAs) may substantially decrease the incidence of acute Hepatitis C in HIV + MSM. This study applies modelling to assess the impact of the rapid uptake of Hepatitis C DAA therapy on the incidence of acute Hepatitis C infection among HIV+MSM in the Netherlands.

In November 2014, all oral DAA therapy became available for F3-4 fibrosis and from September 2015 for F0-2 as well, resulting in rapid DAA uptake in Dutch HIV+MSM with chronic HCV. 65% were cured or on DAA therapy 6 months after unrestricted DAA availability (CROI 2017 Boerekamps et al). Also, in 2014 and again in 2016, individuals with acute Hepatitis C were offered immediate therapy in DAHHS study centres across the Netherlands.

 In 2014, 93 acute infections occurred in 8290 PYFU while in 2016, 49 acute cases were diagnosed in 8961 PYFU. The incidence in 2014 of 11.2/1000 showed a continuous decline to 6.9/1000 and 4.0/1000 within the first and second half of 2016. 1 year after unrestricted DAA availability in the Netherlands, the incidence of acute HCV in HIV+MSM decreased by 52%.

 A delegate enquired whether this reduction may be due to a change in sexual practices of the participants with increased condom use in the era of sexual transmission of Hepatitis C. Review of syphilis and gonorrhoea rates in study participants however, showed a rise in these STIs and would suggest otherwise. Further, next door neighbours Belgium are yet to gain unrestricted access to DAAs and their incidence of acute hepatitis C remains unchanged in recent years. Although the presenter indicated that this modelling study doesnt provide proof, it strongly suggests that for the first time, real-life data shows that HCV treatment as prevention averts new HCV infections in HIV+MSM.

Exciting to document what we think we know! This strengthens the argument to treat acute Hepatitis C in high risk MSM and injecting drug users. The last word went to an American delegate who posed the question to the Dutch presenter: Does this mean you should build a wall between the Netherlands and Belgium?

 

137LB SUBSTANTIAL DECLINE IN ACUTE HCV INFECTIONS AMONG DUTCH HIV+MSM AFTER DAA ROLL OUT

Anne Boerekamps et al

1Erasmus Univ Med Cntr, Rotterdam, Netherlands,

Background: The incidence of acute HCV (AHCV) among Dutch HIV+MSM has been high for >10yrs. Recent modelling studies predict that prompt treatment with direct acting antivirals (DAA) may decrease this incidence substantially (CROI2016 A536) but confirmation from real-life data is awaited. In 11/2014 all oral DAA therapy became available for F3-4 fibrosis and from 09/2015 for F0-2 as well, resulting in rapid DAA uptake in Dutch HIV+MSM with chronic HCV with already 65% cured or on DAA therapy 6 months after

unrestricted DAA availability (CROI 2017 Boerekamps et al). Also, in 2014 (in DAHHS1 study NCT01912495) as well as in 2016 (in ongoing DAHHS2 study NCT02600325) patients with AHCV were offered immediate therapy in DAHHS centers across the Netherlands. We hypothesized that this rapid treatment uptake will result in a lower incidence of AHCV among HIV+MSM.

Methods: AHCV was defined as HCV-RNA positivity, preceded by a negative HCV-RNA or HCV-IgG within 12 months. When stored plasma could not be retested, a normal ALT preceding the first positive HCV-RNA test together with a negative IgG any time in the past or a positive HCV-RNA and a simultaneous negative IgG was also considered diagnostic for AHCV. The incidence of AHCV was calculated by dividing the cases by the patient years of follow-up (PYFU). Data were available from 18 HIV treatment centers, geographically

spread across the Netherlands having +/-80% of Dutch HIV+MSM in care. We compared the incidence in 2014 (year preceding DAA availability) to 2016 incidence (first year after DAA availability).

Results: In 2014, 93 AHCV infections occurred in 8290 PYFU (=11.2/1000 PYFU, 95% CI 9.1-13.7). In 2016, 49 AHCV were diagnosed in 8961 PYFU (=5.5/1000 PYFU, 95% CI 4.17.2, p<0.001). The incidence in 2014 of 11.2/1000 showed a continuous decline to 6.9/1000 and 4.0/1000 within the first and second half of 2016. A relative increase in genotype 4 infections was observed from 19% (n=18) to 31% (n=15) (p=0.02). The absolute number of AHCV infections decreased both in patients with a first AHCV infection as well as in

patients that had an AHCV reinfection (=patients previously cured of an AHCV infection), while the proportion of reinfections remained constant: 21/93 in 2014 and 12/49 in 2016 (p=0.8).

 

Conclusion: 1 year after unrestricted DAA availability in the Netherlands, the incidence of acute HCV in HIV+MSM decreased by 52%. For the first time, real-life data show that HCV treatment as prevention averts new HCV infections in HIV+MSM.

Tagged in: CROI 2017

 Comment: Abstract follows.

For me, this was one of the most interesting studies presented at CROI this year. It generated much discussion amongst delegates and took the post, rather than pre-exposure prophylaxis approach.

STI antibiotic prophylaxis is a topic thats been discussed for decades. Were all struggling to manage the rapid increase in STIs over the past two to three years. Risk compensation is alive and well and our many of our MSM patients frequently present between routine HIV or PrEP visits with symptomatic STIs.

As per my previous blog, the evidence to date for STI antibiotic prophylaxis is limited and the potential costs are high. Of some concern is that antibiotic resistance testing in this study, only pertains to STIs and not other relevant organisms such as malaria and those causing serious skin and respiratory infections.

 The abstract is listed below but Ill end with Jean Michels conclusion slide:

 - PEP with doxycycline reduced the overall incidence of bacterial STIs by 47% in MSM on PrEP (8.7 months of PFU).

- No effect on Gonorrhoea but strong reduction (70-73%) in Chlamydia and Syphilis incidence.

- Acceptable safety profile with mild/moderate GI A/Es leading to discontinuation in only 7% of participants.

- No evidence of risk compensation.

- Analysis of antibiotic resistance pending (STIs only).

- Long term benefots of PEP yet unknown.

- Antibiotic prophylaxis for STIs still NOT RECOMMENDED.

- More research needed in the field of STIs.

 

91LB ON DEMAND POST EXPOSURE PROPHYLAXIS WITH DOXYCYCLINE FOR MSM ENROLLED IN A PREP TRIAL

Jean-Michel Molina et

Background: A high incidence of bacterial sexually transmitted infections (STIs) has been reported in several PrEP trials and demonstration projects among MSM. We wished to assess whether on demand post-exposure prophylaxis (PEP) with doxycycline could reduce STIs incidence in this high risk group.

Methods: High risk adult MSM being followed in the open-label phase of the ANRS IPERGAY trial with on demand TDF/FTC for HIV prevention, were enrolled in a prospective randomized open-label sub-study. Participants (pts) were randomized 1:1 to take either two pills of doxycycline (100mg per pill) within 72h after condomless sexual intercourse (without exceeding 6 pills per week) or no PEP. All subjects received risk-reduction counseling and condoms, and were tested every 8 weeks for HIV and STIs with serologic assays for HIV and syphilis and PCR assays for Chlamydia trachomatis and Neisseria gonorrhoeae in urine samples, oral and anal swabs. The primary study endpoint was the time to a first bacterial STI: gonorrhoea, chlamydia infection or syphilis. We compared the two study arms according to the intention-to-treat principle. We used time-to-event methods, including KaplanMeier survival curves and Cox proportional-hazards models.

Results: From July 2015 to January 2016, 232 pts were randomized, 116 in each arm. Median follow-up was 8.7 months (IQR: 7.8-9.7). Seventy-three pts acquired STIs during the study period, 28 pts in the PEP arm (24%, 37.7 events per 100 pt-years) as compared to 45 pts in the no PEP arm (38.8%, 69.7 events per 100 pt-years) for a hazard ratio (HR) of 0.53 (95% CI: 0.33-0.85, P=0.008). HR for gonorrhoea, chlamydia infection and syphilis were 0.83 (95% CI: 0.47-1.47, p=0.52), 0.30 (95% CI: 0.13-0.70, p=0.006) and 0.27 (95% CI:

0.07-0.98, p<0.05), respectively. Overall 71% of all STIs were asymptomatic. Pts in the PEP arm used a median of 7 pills/month (IQR: 3-13). Safety was good with only 8 pts (7%) discontinuing PEP because of gastro-intestinal adverse events (AEs). Gastrointestinal AEs were reported in 61 pts (53%) and 47 pts (41%) in the PEP and no PEP arms, respectively (p=0.07). There was no significant change in sexual behaviour between study arms during follow-up.

 

Conclusion: On demand PEP with doxycycline reduced the incidence of chlamydia infection and syphilis in high risk MSM and has an acceptable safety profile. The long-term efficacy of this strategy and its impact on antibiotic resistance needs to be assessed.

Tagged in: CROI 2017

 

A few “Snapshots” from the Inflammation and Age-related Complications session, of interest:

 

1.       An update of D.A.D. data looking the association of cardiovascular disease and contemporarily used protease inhibitors, Atazanavir and Darunavir: Analysis looked at a prospective 7 years’ median follow-up (IQR 6.3 – 7.1) of 35,711 participants with 1,157 (3.2%) of participants having cardio and cerebro-vascular events (incidence rate 5.3/1000 PYFU (95% 5.0 5.6).  The analysis, with which we are now familiar, looked at crude incidence rates of CVD per 1000 PYFU stratified by cumulative use of ATV/r and DRV/r, and MI and Stroke separately. In this analysis, the cumulative use of DRV/r, but not ATV/r was independently associated with a small but increasing risk of 59% per 5 years’ exposure. The strength of the association is of a similar size for the older PIs but in contrast, does not appear to be modified by dyslipidemia.  We were reminded to exercise caution in interpretation as the study is observational only, and there are risks of unmeasured confounding. (L. Ryom et al CROI 2017 # 128LB.)

 

2.     Investigators in the North American AIDS Cohort Collaboration on Research and Drugs (NA ACCORD) looked at the incidence occurrence of Type 1 MI (atherothrombotic coronary event from plaque rupture) and the association with modifiable traditional risk factors by analysing the Population Attributable Factors (PAF) for MI.  They concluded that 43% of cases of MI in this cohort could have been avoided if these individuals did not have an elevated cholesterol, holding all other variables constant, 41% of MI were avoided by treating hypertension and 38% by smoking prevention. (K. Althoff et al CROI 2017 # 130.)

 

3.       A further analysis from the D.A.D cohort looked at cessation of cigarette smoking and the impact on cancer incidence. (N= 242 cases of lung cancer, and N=487 cases of smoking related cancers, excluding lung).  There were limitations in the study relating to the collection of cessation dates, intensity, duration or pack years unfortunately. However, the investigators concluded that smoking related cancers, excluding lung cancer, rapidly declined following cessation. Lung cancer incidence appeared to remain elevated in HIV patients several years after cessation, which is in contrast to studies in HIV negative individuals. (L. Shepherd et al CROI 2017 #131.)

 

Tagged in: CROI 2017

 

Venous thromboembolism (VTE ) risk is increased in HIV patients (5.7 -11.00/1000 person years) compared to the general population (1.0/1000 person years, with all data predating 2003. C. Rokx et al aimed to look at VTE in the current era in the Dutch Athena cohort with data between 2003-2014 on 14,386 patients.202/229 first VTE occurred in proximal leg veins or pulmonary arteries and 153/202 had withdrawn anticoagulants. 32 recurrent VTE occurred (59 VTE/1000person years; 95% CI; 41-83). Kaplan-Meier recurrence rates at 1, 2 and 5 years of follow-up were 16% 19% and 28% following unprovoked first VTE. When CD4 cell count is above 500, VTE incidence approaches that of the general population. Conclusion: Patients with persistent low CD4 cell counts might benefit from longer anticoagulant therapy. C Rokx et al, CROI 2017 Abstract #620.

 

I have seen a number of HIV patients with VTE over the years, the last being 2 months ago with the major concern at the time being a potential drug-drug interaction.  So, what new information was available at CROI regarding that drug-drug interaction?

 

As you are all aware, Ritonavir (RTV) and cobicistat (COBI) are antiretroviral pharmacokinetic (PK) enhancers that can inhibit several drug transporters, including P-glycoprotein (P-gp) and renal multidrug and toxin extrusion-1 (MATE-1). Dabigatran etexilate DE (trade name Predaxa) is the prodrug form of the oral direct thrombin inhibitor, dabigatran, and is a substrate for these transporters. Kristina M. Brooks and colleagues conducted a single centre open-label fixed sequence PK study on 16 healthy volunteers to evaluate the effects of separated and simultaneous administration of RTV and COBI on dabigatran PK. Findings: No significant changes in dabigatran exposure were observed with simultaneous RTV administration, possibly due to mixed induction and inhibition of P-gp by RTV. However, COBI resulted in significant increases in dabigatran exposure that persisted despite separating administration, most likely due to intestinal P-gp inhibition. These findings suggest RTV and DE can likely be co-administered, whereas the use of DE and COBI may require reduced dosing and careful clinical monitoring. K. Brooks et al CROI 2017 # 409. My patient is continuing to do well on Dibigatran (normal dose) and Genvoya. We will see Dabigatran used more often in HIV patients with thrombo-embolic disease.

 

 

 

 

 

Tagged in: CROI 2017

So far there have been two well documented cases of individuals on PrEP contracting HIV despite good adherence and high TDF levels. This poster presents a case where a 50 year old gentleman, who had optimal TDF levels (on 2 dried blood spot examinations) - 8 months in to the AMPrEP study he tested antibody reactive, antigen negative on a 4th generation Ab/Ag HIV test. During this visit he described symptoms of fever and dysuria. Western blot reveleaved a single band at gp160. At the time the patient had tested negative on pol PCR (DNA and RNA) of bulk PBMCs and sigmoid colon biopsy, and had no detectable HIV viral load. PrEP was subsequently stopped due to concerns around inducing resistance (looks like this was done within a few days of the results - see attached poster). 3 weeks later, HIV RNA was detected in plasma (40,000 copies/ml). No resistance mutations were identified. The patient was commenced on treatment and 1 month later had an undetectable viral load.

 

The presenter highlights this as being a probable third case of HIV seroconversion in a PrEP-adherent individual. This would be a first case of wild-type virus being transmitted under these conditions. They postulate possible reasons for PrEP failure such as very high exposures, and repeated trauma.

 

What’s not clear to me is whether the possibility of a false reactive HIV Ab/Ag was considered. The poster does not detail the reactivity score (i.e. was this a borderline result) on the LIAISON XL platform. If this result was a borderline reactive, was this more of a PEP failure, i.e. the patient did not have a long enough PrEP-tail following last UPAI, or was this indeed a PrEP failure? Did they stop the PrEP too soon? This brings us to question how we go about managing indeterminate HIV results in the the context of PrEP.

 

What do you think?

Tagged in: CROI 2017

I tried something a little different this afternoon. The conference venue set up a simulcast of all concurrent sessions in a theatre-like venue with six screens displaying the slides from each session. Audio was provided by personal channel-selected headphones, much like the system used in some gymnasiums broadcasting TV audio to users. It was a great way to flick between sessions rather than having to run between rooms. Despite this great technology, the human limitation still applies, and you can only pay attention to one presentation at a time!

The themed discussion afternoon consisted of 4 or 5 short presentations, following by robust discussion with the audience. The session on CNS treatment strategies addressed the issue about HIV and the CNS, in particular the issue of the potential for neurocognitive deficits to persist despite apparent complete viral suppression on ART. This effect is likely due to reservoir seeding to a sequestered site, resulting in ongoing immunogenitic and inflammatory effects of HIV, as discussed at other points at the conference.


The CNS is an early target for HIV. HIV-associated Neurocognitive Disorder (HAND) encompasses the spectrum of disorders related to HIV infection and AIDS, and includes disorders of varying severities. What is known is that early identification and treatment improves HAND, and ART improves established HAND.

A study into whether delays in ART initiation would impair neurocognitive function compared initiation immediately after infection with a 24 week delay. Interestingly, early initiation led to a greater improvement in neurocognitive function over time. The observation has important implications to clinical practice and in discussions with patients about when to start treatment. Early ART initiation may prove to be an important treatment strategy to decrease the severity of HAND or lead to better improvement in HAND.  [TD-380]


 

The next presentation looked at the cognitive trajectories over 4 years of HIV positive women with optimal viral suppression. There was a lower baseline cognitive function in several neurocognitive domains (attention, learning, memory and global functioning) in the HIV infected group compared with demongraphically similar uninfected women. The difference observered was at least one standard deviation worse across these domains and persisted over time. In the domain of motor skills, where there was no difference at baseline, a decline was observed over the 4 year period.

In comparing women who were virally suppressed with those that were not, in some domains (eg. global function) there was no difference in the measured decline over time. Interestingly, in some domains (eg. attention and fluency) virally suppressed women actually performed worse than non-virally suppressed women.

The difference at baseline may be attributed to co-morbidities such a susbtance use, trauma and psychological risk factors. These, combined with a low cognitive reserve, are hypothesised to be contributing to accelerated CNS ageing.

The vulnerabilities in various neuropsychological domains provides a framework for further study into the pathophysiology of the CNS damage observed. Clinically it is important to understand how co-morbidities in HIV infected individuals may be contributing to the HIV specific effects.  [TD-350]


 

CCR5 blockade using Maraviroc intensification has been shown to improve cognitive performance in HIV infected adults on ART. CCR5 binds multiple chemokines and is a co-receptor for HIV.

Cenicriviroc (CVC) is an new oral dual CCR2 and CCR5 antagonist. CCR2 is a chemokine receptor for the monocyte chemoattractant MCP-1. Monocytes have been implicated with contributing to HIV-associated Neurocognitive Impairment (HIV NCI). In ART naive HIV infected adults, CVC has been shown to decrease viraemia and soluble CD14 levels (CD14 is a marker for monocyte activation). Additionally, in animal models CVC has been shown to have anti-inflammatory and anti-fibrotic activity.

The pilot study hypothesised that CVC will improve cognitive function in HIV NCI by reducing monocyte activation. The sample cohort was older (average age 55), ART experienced (average 16 years on ART) and had low cognitive performance at baseline. Depression was an exclusion criterion. Neuropsychological testing was conducted at entry and at 24 weeks, along with plasma markers of monocyte activation (neopterin, soluble CD14 and sCD163).

The study observed that CVC intensification improved global cognitive performance, along with specific improvements in the neurospsychological subdomains of working memory and attention. There was a positive trend seen in the domains of psychomotor speed and visuospatial. Monocyte activation was significantly decreased with all three markers measured, with a trend seen between neopterin and working memory scores.

Although only a small study (17 participants) the results are certainly promising. Even in virally suppressed, ART experienced individuals, the measured improvements in cognitive function at 24 weeks suggests that HIV NCI may be treatable. Additionally, neopterin may be a predictor of improvement in working memory. A larger randomised control trial in HIV infected people with cognitive abnormalities is required to explore these effects further.  [TD-381]

Tagged in: CNS CROI 2017 HAND

 

Day 3 CROI:

 

I am sure all the General Practitioners reading this topic are much more familiar with the management of patients with this condition than I am. 

 

Dr Rohit Loomba is a Gastroenterologist/Hepatologist at University of California, San Diego and he presented current work he, and colleagues, are undertaking in imaging and monitoring patients long term with NAFLD (Non- Alcoholic Fatty Liver Disease) and progression to NASH (Non-Alcoholic Steatohepatitis): Defined as >5% fatty infiltration on liver biopsy with pathognomonic ballooning of hepatocytes. NASH is now the second cause of liver transplantation in California.

 

NAFLD is divided into NAFL (non-progressive over many decades) and NASH (rapidly progressive over 7-8 years with a high mortality rate).

 

Some of the identifying clues to a patient with NAFLD are:  Metabolic Syndrome, Diabetes mellitus, older age, high AST/ALT, low platelets and low albumin. For these patients consider Hepatologist assessment for liver biopsy and appropriate imaging.

 

We are all aware that patients with HIV have increasing mortality due to liver disease. Dr Loomba indicated that NASH is 30-40% higher in patients with HIV infection and is independent of age, sex and BMI. He is currently looking at appropriate imaging strategies for NASH which monitor impact on pericardial fat and loss of muscle mass with progressive NASH. Sarcopenia is associated with increased mortality. His unit is also currently undertaking trials with a new medication Aramchol together with lifestyle intervention and weight loss strategies

 

TAKE HOME MESSAGE: We all need to be more proactive in assessing HIV infected patients with “fatty infiltration” of the liver on ultrasound especially if they have other associated clinical parameters.

 

Tagged in: CROI 2017

           Cerebral small-vessel disease (CSVD) is a common problem with increasing age and accounts for approximately 20% of strokes and 45% of dementia. In addition to age, hypertension is a major risk factor for the development of CSVD.  CSVD is characterised by white matter hyperintensities, silent infarcts and microbleeds.

           This cross sectional study examined the prevalence of CSVD in PLHIV (who immunovirologically controlled for at least 2 months on cART), comparing them with age and sex matched controls. A 3T MRI scanner was used and the diagnosis of CSVD was made by 2 neuro-radiologists who were blinded to serostatus.

           After adjusting for known risk factors, the prevalence of CSVD was twice higher in middle aged PLHIV (aOR 2.3).

           This study adds to the continually growing list of conditions that are more common in PLHIV, even where they are immunovirologically controlled. This therefore leads us to the question of how we go about managing or mitigating this effect. I did some further reading around up-to-date guidelines on CSVD. It seems that aside from managing blood pressure, there is little evidence to support the routine use of other agents, including statins or anti-platelets. These studies however have been done primarily in HIV negative individuals. The pathophysiological mechanisms underlying (at least some of) CSVD in PLHIV may be different. Given the extensive interest in the anti-inflammatory effects of statins in HIV, one wonders whether there may be a role in managing CSVD.

Tagged in: CROI 2017

Comment:

The significant rise in symptomatic and asymptomatic STIs in recent years is having a huge impact on clinical practice. Many practices struggle to manage additional presentations to test and treat those with STI symptoms and to organise treatment and followup of those with positive test results. I have also noted an increase in requests from MSM on PrEP for private Doxycycline scripts for syphilis prophylaxis.

A number of trials are underway to address the topic and it's important to acknowledge that, at present the evidence is minimal. The list of potential adverse consequences is however, a lengthy one.

The rate of HIV resistance in those who acquire HIV while taking PrEP is small..... but we're only focussing on one pathogen. There are numerous bacteria in different organ environments upon which Doxycycline prophylaxis may have an impact. While there are concerns about emerging bacterial resistance in STIs such as Gonorrhoea and Mycoplasma Genitaleum, it is essential that we explore resistance in other organisms at other sites to fully characterise the problem.

Further, intermittent antibiotic use may alter the clinical course of infection (eg Mycoplasma Genitaleum) and partially treat STIs such as syphilis, confusing interpretation of results and management issues further.

The vaginal and penile microbiome have been discussed at several sessions at CROI, and I also wonder what impact antibiotic use may have on such microbiota, and whether this could increase HIV transmission (eg BV being linked to increased transmission)?

This is an important topic and worth understanding some of the complexities so that we can educate individuals seeking prescriptions now, in the absence of evidence.

 


I've summarised Jean Michel Molina's presentation below:

55 ANTIBIOTIC PROPHYLAXIS FOR STIs: PROMISES OR PERILS

Jean-Michel Molina,

 Globally, more than 1 million STIs are acquired daily, and annually approximately 146 million of new infections with chlamydia, 78 million of gonorrhoea and 6 million of syphilis are diagnosed. In the US, 2015 was the second year in a row with an increase in STIs, with syphilis increasing at an alarming rate among MSM. Implementation of PrEP for HIV prevention has also highlighted the increasing incidence and prevalence of STIs in PrEP users.

 Current efforts to contain the spread of STIs are obviously not sufficient and should include:

              - promotion of condom use.

              - counselling and behavioural interventions.

- vaccinations for viral STIs (Hep A and B, HPV).

- scaling up more effective STI service.

- increased testing for STIs in high risk individuals for early diagnosis of symptomatic and asymptomatic infection.

- better notification and treatment of sex partners.

- new biomedical interventions: Antibiotic prophylaxis?

 

The success of PrEP for HIV has raised interest in biomedical interventions for STIs. Pending the development of vaccines against bacterial STIs, the potential role of antibiotic prophylaxis should be re-assessed.

Studies conducted by the military have shown the short-term efficacy and the limitations of post-exposure prophylaxis. More recently, periodic presumptive treatment in female sex workers with azithromycin alone or in combination have shown reduction in incidence of gonorrhoea and chlamydia but not of syphilis or HIV. Mass treatment with azithromycin for trachoma and Yaws elimination has also shown some impact on STIs prevalence.

Studies using doxycycline prophylaxis for syphilis in high risk MSM are ongoing. Should antibiotic prophylaxis be successful at reducing STIs incidence, the short-term benefits should be balanced against the potential for adverse consequences:

 

              Short term reduction in STI prevalence with rebound to pre-intervention rates:

              - Selection of antibiotic resistance.

              - Change in sexual behaviour/risk compensation.

              Changes in STI presentations:

              - Prolongation of the incubation period (delayed seroconversion).

              - More frequent asymptomatic carrier state with extragenital locations.

              - Emergence of new STIs resistant to chemoprophylaxis (eg Mycoplamsa Genitaleum).

              Selection of antibiotic resistance:

              - Selection and clonal dissemination of drug resistant STIs.

              - Reduction of already limited treatment options.

              - Impact on human microbiome: Drug resistance in other pathogens (eg Staph Aureus)

              Tolerability

              Cost

 

New strategies need to be developed to contain the spread of STIs. Antibiotic prophylaxis for bacterial STIs in high risk populations should be carefully evaluated.

Wednesday morning featured a series of oral presentations exploring the interplay of STIs and altered microbiomes might affect PrEP.

Renee Heffron presented research that explored whether bacterial vaginitis decreased the effectiveness of oral PrEP.

In the CAPRISA 004 study which demonstrated the effectiveness of intravaginal tenofovir it was observed that in women that had a vaginal biome consistent with BV there was a significantly decreased effectiveness of vaginal tenofovir gel. It is postulated that anaeobic bacteria may hasten the breakdown of tenofovir. This study explored data from the PARTNERS PrEP study .  It compared baseline vaginal swabs , graded using the nugent scale as to the number of BV related bacteria, with serum tenofovir levels and HIV seroconversion. Reassuringly BV did not seem to affect either Serum levels or PrEP effectInness.

 

John-Michel Molina presented an interesting IPERGAY sub study. This looked at the controversial area of STI prevention using Doxycycline PEP. Men enrolled in IPERGAY were randomised to be provided with doxycycline PEP or not provided with PEP. Those asked to take the doxycycline PEP were asked to take a stat dose of 200mg between 1 and 3 days after sex. The time to acquisition of an STI (gonorrhoea , chlamydia or syphilis) was compared. In brief , no effect on gono but significantly reduced rates of syphilis and chlamydia. The data presented didn't address the thorny issue of antibiotic resistance. They are still looking at that.

 

Tagged in: CROI 2017
Site visit to Magnet Clinic- Castro St, San Francisco.

Magnet is a nurse and peer led Sexual Health service in San Francisco. It recently co-located with Strut (San Francisco AIDS Foundation) and a number of other organisations working in the sector. I was warmly welcomed by Joshua O’Neill (HIV Testing Services Manager) and Pierre Crouch (Nurse Director).

The clinic opens 6 days a week and provides the following services:

-    Free STI testing and treatment on site and in mobile units around the city. The mobile clinics occur 3-4 times/week and with a bacterial STI pick up rate of approximately 8-10%, they provide an invaluable service to those who do not access mainstream STI services. Rapid HIV and Hep C (Ab) testing are also offered. 

-  PEP is offered free of charge. 

         -   PrEP is provided to individuals through several sources. Depending on health insurance status, PrEP may be funded under an individual’s health care plan. For those with inadequate or no private health insurance, Magnet has health insurance navigators to assist the process. Like in Australia, a high proportion of individuals import PrEP via the internet. Magnet is also a part of a double blinded RCT of 5000 HIV negative MSM randomised to receive either Truvada or F/TAF as daily HIV PrEP. This trial is not being conducted in Australia. 

       - Under the Stonewall project offered by Strut, free individual or group counselling for support regarding drug or alcohol use. 

          - An art gallery and lounge aiming to promote the physical, mental and social well-being of gay men. 

          - Social events for a variety of groups including transgendered and African American MSM.

          - STI testing and access to emergency HIV medication, PrEP or PEP to those visiting from abroad (no charge for a one month supply)

 

 Take home messages from the visit:

 1.     Mobile STI screening units provide an excellent way to reach MSM who may not access traditional STI testing and treatment services. With an STI pick up rate 8-10%, they create an excellent opportunity not only to diagnose and treat bacterial STIs, but also to reduce the number of undiagnosed people living with HIV. The benefits to both the individual and the community are obvious. 

2.     Australian’s visiting who have misplaced their HAART or PrEP, or those who require PEP while away, are most welcome to attend the clinic and will be offered a free 4 week supply of medication. It’s worth knowing about this as many of our patients travel to San Francisco.  

3.     The staff have hosted a number of international visitors in recent years and they welcome the opportunity to show health professional services when visiting San Francisco.

 

 

 

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Symposium 5-3 ‘Strangers in the Night; Challenges and Opportunities in STI Control: provided a fascinating insight into potential opportunities and strategies for STI control. There was so much interesting and important information in the two hours of the session that I encourage to take the time to watch the whole webcast of this session.

 

R. Scott McClelland presented on the ‘Vaginal Microbiome and Susceptibility to HIV’ addressing the dynamic changes in the vaginal microbiome and the conditions, eg Bacterial Vaginosis, that can lead to morbidity and increased risk for HIV entry.  Jean-Michel gave a historical overview of the outcomes and opportunities for ‘Antibiotic Prophylaxis for STIs: Promises or Perils’ – you are left feeling that the risk of antibiotic resistance (eg as has occurred with gonorrhoea) is far too great for future intervention with prophylactic antibiotics for STIs.

 

Matthew Golden outlined the experience in USA (and Australia) in relation to the increasing rates of STIs in ‘Syphilis in the Era of Treatment as Prevention and Pre-Exposure Prophylaxis’.  He addressed the various changes in sexual behaviour eg serosorting, rates of condom use and sex in the era of PrEP and warned that we must address the increased rate of STIs, particularly syphilis in MSM, with renewed vigilance.  Lastly, Rebecca Guy from the Kirby Institute addressed the challenges of the ‘Scale up-of Point-of Care Tests for Sexually Transmissable Infections’ addressing the sensitivity of available tests, and their appropriate use.  Rebecca outlined the Kirby Institute’s projects in antenatal clinics in PNG and with community sexual health workers in remote Australia. The implementation of POC tests with the aim of treatment on the same day, by staff in those settings was outlined.

 

 

 

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Day 2 CROI

My colleagues have already commented on the new HIV integrase strand transfer inhibitor, Bictegravir, so onto other potential new agents/formulation:

Presented by Gilead, the HIV Capsid Inhibitor was discussed in relation to its antiviral activity and proof of concept work. The Capsid Inhibitor, GS-CA1, is a first in class. The agent acts at multiple sites in the HIV life cycle - at the assembly site of the capsid core essential for the virion and at the disassembly site of the capsid which is necessary for nuclear translocation after reverse transcriptase. The capsid inhibitor binding site is highly conserved.  The capsid inhibitor associated mutations map exclusively to the inhibitor binding site.

The EC 50 = 140 picamolar. With the activity of GC-CA1 a defective virion is produced that is non-infectious. The agent is active against all HIV1 clayds (slightly less potent against HIV2). So far, PK data in rats is maintained over ten weeks, leading to a proof of concept for monthly injectable dosing and is ideal for low dose, long acting administration.

CS-CA1 is currently in a preclinical programme.

Nanoparticle antiretroviral formulation was broadly outlined in relation to two ARVs, Efavirenz and Lopinavir (the agents were chosen in 2009, so are not necessarily in line with current ARVs).  In principle, nanoparticle formulation has two benefits: it allows for lower dosing of dry nanoparticle formulations and can be used for Paediatric formulations as they can be dispersed in water. The data thus far, confirms potential for a 50% dose reduction while maintaining therapeutic exposure for a future novel combination ARV.

One final comment in this session on ARVs: Jose L Balanco et al presented on the pathways of resistance in subjects failing Dolutegravir monotherapy. It was noted that selection of genotypic resistant mutations was rapid. The Chairman noted that Dolutegravir is not approved by the regulatory body for use in monotherapy and expressed some disquiet as it appears that consent was not obtained from all patients. Refer a recent article in Antiviral Therapy (?end of 2016) on ethical issues and monotherapy.

 

 

 

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  1. Since the advent of integrase inhibitors, bringing about our latest highly effective combination therapy, with viral suppression rates approaching 97%+, many clinicians have questioned a place for new antiretrovirals. How do we get much better? Will there be any compelling reasons to switch our patients to newer agents? In addition, studies such as SWORD have shown simplification strategies can be highly effective, using exisiting drugs, without the need for a third agent. Studies examining cabotegravir, a long-acting integrate inhibitor which can be given as a depot injection, have now entered phase 3 clinical trials, which may possibly negate the need for daily oral treatment. So what does this mean for future drugs? How will they find their niche in what is becoming a rather crowded market? I think given the aforementioned advances, new drugs will need to be highly effective, have high genetic barriers to resistance, thus possibly lending themselves to either dual or monotherapy. Additionally, long-acting drugs which may be able to be given less frequently (through depot or implant), may have an important role in the future of ART. Finally, drugs with novels modes of action, may have a continued role in treatment experienced patients with resistant virus.

     

    This presentation from Gilead Sciences (abstract below) introduced a novel first-in-class capsid inhibitor which leads to a defective HIV-1 virion through interference in the capsid core assembly. In-vitro assays have revealed CS-CA1 to be a highly potent drug with no measurable toxicity in target and non-target cells. The drug binds to a largely conserved region on the capsid protein. In addition, the drug appears to have activity blocking some of the post-entry capsid functions. Pharmacokinetic studies in rats have demonstrated sustained plasma concentrations and the drugs limited aqueous solubility make a drug possibly well suited to long-acting depot administration.

     

     

    I feel that this novel drug offers exciting promise, especially if the in-vitro activity translates to highly effective antiviral activity in-vivo - possibly leading to a long-acting drug lending itself to simplified depot administration.

     

    DISCOVERY OF NOVEL POTENT HIV CAPSID INHIBITORS WITH LONG-ACTING POTENTIAL
    Winston C Tse
    , John O. Link, Andrew Mulato, Anita Niedziela-Majka, William Rowe, John R. Somoza, Armando G. Villasenor, Stephen R. Yant, Jennifer R. Zhang, Jim Zheng

    Gilead Scis, Inc, Foster City, CA, USA

    Background: While HIV capsid (CA) plays an essential role in multiple stages of the viral life cycle, it remains an unexplored target for antiretroviral (ARV) therapy. Here, we report the discovery of a novel class of exquisitely potent and metabolically stable HIV capsid inhibitors (CAIs) that exhibit pharmacokinetic (PK) profiles suitable for slow-release parenteral administration.
    Methods: In vitro CA binding and assembly assays, together with X-ray co-crystal structures of CAIs with cross-linked CA hexamers, were used to optimize compounds for
    high binding affinity to CA. Medicinal chemistry approaches were employed to optimize the antiretroviral activity and drug-like properties using a cytopathic antiviral assay in conjunction with extensive metabolism and pharmacokinetic profiling. CAI resistance-associated mutations were identified by in vitro resistance selections. CAI mode-of-action was defined by inhibitor time-of-addition, virion electron microscopy and viral DNA quantification.
    Results: GS-CA1, an exemplified member of a novel class of CAIs, is a highly potent inhibitor of HIV-1 replication in T cell lines (EC50 = 0.24 nM) and displays similar potency against multiple HIV-1 clinical isolates from all major clades in human PBMCs. Identified CAIs bind to a broadly conserved site at the interface of two adjacent monomers within a CA hexamer and accelerate CA assembly in vitro. The identified CAIs maintain full activity against HIV-1 mutants resistant to licensed ARVs and select for HIV CA variants L56I, M66I, Q67H or N74D with an attenuated in vitro replication phenotype. Mechanistic studies revealed a dual mode of action targeting both the late-stage virion maturation and post-entry CA functions. GS-CA1 shows high in vitro metabolic stability and favorable PK profiles in multiple preclinical species with low systemic drug clearances (0.08–0.33 L/ hr/kg) and long half-lives (7.2–18.7 hr). Low aqueous solubility provides for an extended-release preclinical PK profile following subcutaneous administration of a solid depot formulation.
    Conclusion: We have identified novel HIV-1 capsid inhibitors with uniquely potent antiviral activity and a favorable resistance profile orthogonal to existing ARVs. The high metabolic stability and low aqueous solubility of this new inhibitor class should enable the development of an extended-release parenteral formulation with the potential to be used as a novel long-acting antiretroviral treatment. 

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Tuesdayy afternoon provided a session of poster presentations exploring the complicated relationship between ARV treatment , excess weight gain and hepatic steatosis.

In summary ,

Weight gain in an HIV positive male is associated with twice the diabetes risk of the same degree of weight gain in an HIV negative male

Amit Achra from Kirby Institute presented DAD data the relationship between BMI and non AIDS related adverse outcomes. The results suggested that for CV risk both very low BMI (<18) and very high BMI (>30) were associated with an increased risk , and for non AIDS related cancers , risk was significantly associated with very low BMI and very high BMI.

An exercise physiologist from Massachusetts presented a study where overweight HIV positive patients were randomised to either be enrolled in an online weight loss and health coaching program or be in a control arm with minimal weight loss suppport. The results suggested the program was both cheap to run and successful in terms of significant weight loss.

A retrospective  analysis of a study where naive patients were randomised to start either raltegravir, boosted atazanavir or boosted darunavir plus 2 nucs looked at the predictors of excess weight gain. Interestingly they were black race , higher baseline disease severity and use of Raltegravir. There was a lot of discussion about the possible explanation of Raltegravir falling out as a predictor.

Interestingly a study was presented were HIV positive women on NNRTI or PI based regimens were randomised to either stay on th regimen or swap to Raltegravir regimen. They looked a biochemical markers of hepatic steatosis , Chi3L1 and adipokine adiponectin. It was interesting that both these markers droped (suggesting decreased steatosis) in those that switched to Raltegravir.

Finally a study looking at patients swelling from a Efavirenze containing regimen to a Raltegravir regimen appeared to decrease their steatosis as measured by a CAP score, (Controlled Attenuation Parameter , an add on process done with a fibrous scan)

So Raltegravir seemed to lead to weight gain but less hepatic steatosis , a result that seems to pose more questions than it answers.

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Dr Carl June presented how novel therapeutics have the potential for an HIV cure. His work in the development of Chimeric Antigen Receptor (CAR) T cells have been instrumental in the cure of lymphoid malignancies. There are similarities in CD4 cell dysfunction between cancer, which causes exhaustion of T cells, and HIV, which causes deletion of HIV specific cells.

CAR T cell therapies use synthetic biology, tools of genetic engineering and genome editing to install a competent immune system into an immunocompromised host. In cancer therapy, an individual's T cells are harvested and geneticically engineered to make the T cells stably express CAR, conferring novel antigen specificity. They are reinfused into the patient to become personal "serial killer" cells. In almost 400 patients accumlating 1500 patient years, there have been no acute T cell toxicity events (ie. no conversion to acute leukaemia). Success has been seen out to 5 years with complete cure of a paediatric patient with advanced ALL and an older adult with extensive CLL.

Unfortunately there are no CAR T cell trials in HIV currently in progress, but it is likely to be an area of future research, with work towards an HIV cure.

The issues faced with this sort of technology are based around time, cost and the need for an individual's cells to be genetically engineered for each patient. Consideration of a blood bank model or central manufacturing strategy could advance implementation. Automated genetic engineering methods could allow CAR T cell treatments to be scalable, with lower coats and increased access. A government-industry-philanthropic partnership for combined funding could be a way ahead.

Links to:
Video and slides
Audio and slides
Audio only

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Comment: Abstract follows:

Doravirine seeks to address the limitations of the currently available NNRTIs: avoidance of neuropsychiatric side effects, no food requirements or concerns re co-administration with antacids/PPIs, fewer drug-drug interactions and a once daily option with a higher genetic barrier to resistance than efavirenz or rilpivirine.

83.8% (321/383) of subjects on the doravirine arm had an undetectable viral load at week 48 when compared to the darunavir/r arm  79.9% (306/383). When comparing this to the phase II F/TAF/BIC versus F/TAF/DTG data presented earlier this session (97% and 91% respectively), I wonder what role doravirine will play in the treatment naïve setting. Ideally a treatment naïve phase III trial comparing doravirine to an integrase inhibitor such as dolutegravir would help to answer this question. 

Perhaps it will find a place as a once daily salvage option?

 

45LB DORAVIRINE IS NON-INFERIOR TO DARUNAVIR/R IN PHASE 3 TREATMENT-NAIVE TRIAL AT WEEK 48

Jean-Michel Molina et al

Background: Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with once-daily dosing and potent in vitro activity against the most common NNRTI resistant variants (K103N, Y181C, G190A). In a phase 2b study, DOR 100 mg once daily (QD) demonstrated similar efficacy to efavirenz, with favourable safety and tolerability through Week 48.

Methods: DRIVE-FORWARD is an ongoing, phase 3, multicenter, double-blind, non-inferiority trial in antiretroviral treatment-naive adults with HIV-1 infection and pre-treatment HIV-1 RNA 1,000 c/mL. Participants were stratified by screening HIV-1 RNA ( or >100,000 c/mL) and investigator-selected NRTI backbone therapy (TDF/FTC or ABC/3TC) and randomized in a 1:1 ratio to receive DOR 100 mg QD or darunavir 800 mg with ritonavir 100 mg (DRV/r) QD, in combination with the selected NRTI, for up to 96 weeks. The primary endpoint was the proportion (%) of participants achieving HIV-1 RNA <50 c/mL at Week 48 (NC=F, FDA Snapshot approach) with predefined non-inferiority margin of 10%. A secondary objective was to evaluate the effects of DOR and DRV/r on fasting serum lipids.

Results: Of 769 participants randomized, 766 (383 in each group) received study drug and were included in the efficacy and safety analyses (mean age 35.2 years, 84% male, 73% white, 87% on TDF/FTC). DOR was non-inferior to DRV/r on the primary endpoint, with 83.8% (321/383) and 79.9% (306/383), respectively, achieving HIV-1 RNA <50 c/mL at Week 48 (difference 3.9%, 95% CI [-1.6, 9.4]). In the subgroup with baseline HIV-1 RNA >100,000 c/mL, 81.0% (64/79) on DOR and 76.4% (55/72) on DRV/r achieved HIV-1 RNA <50 c/mL at Week 48 (OF approach). Adverse event rates (overall, serious, drug-related, and leading to treatment discontinuation) were similar across treatment groups. The most common drug-related AEs (>5% in one or more treatment groups) were diarrhea (5.5%, 12.8%), nausea (6.5%, 7.6%), and headache (6.0%, 2.6%) for DOR and DRV/r, respectively. Fasting LDL-C and non-HDL-C were reduced by DOR and increased by DRV/r (see table) with statistically significant treatment differences (p<0.0001).

Conclusion: At Week 48, DOR demonstrated potent efficacy and was non-inferior to DRV/r on a background of 2 NRTIs in HIV-1 treatment-naive adults. Efficacy was similar regardless of baseline HIV-1 RNA. DOR was generally safe and well-tolerated with a superior lipid profile for fasting LDL-C and non-HDL-C compared to DRV/r.

 

 

 

 

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Comment: Abstract follows:

This study demonstrates non-inferiority of treatment switch to dolutegravir/rilpivirine at 48 weeks versus remaining on current antiretroviral therapy. Its satisfying to hear in person, data presented from a trial being conducted at our site.

Since 1996, triple therapy has been standard of care in treating HIV. As the HIV population ages, we are increasingly concerned by the potential toxicities associated with either TDF or abacavir use. While the development of TAF attempts to address this important clinical issue, its exciting that NRTI limiting strategies are also being pursued as an alternative strategy.

 Given its high genetic barrier to resistance, dolutegravir is an obvious candidate to explore this strategy and in addition to this study, late-breaker data regarding dolutegravir as maintenance monotherapy (Poster 451LB) will be presented in the coming days. A study of cabotegravir/rilpivirine as oral maintenance therapy is also being presented (Poster 442). 

 

44LB PHASE III SWORD 1&2: SWITCH TO DTG+RPV MAINTAINS VIROLOGIC SUPPRESSION THROUGH 48 WKS

Josep M. Llibre et al

Background: The requirement for life-long antiretroviral therapy (ART) of HIV infection has highlighted interest in 2-drug regimens (2DR) to minimize cumulative drug exposure. Dolutegravirs (DTG) potency, safety and resistance barrier make it an optimal core agent for 2DR. Rilpivirines (RPV) safety, tolerability and efficacy in switch regimens make it an ideal potential partner.

Methods: Two identical open-label, multicenter, global, phase III, non-inferiority studies evaluated the efficacy and safety of switching from a 3 or 4-drug current antiretroviral regimen (CAR) to DTG+RPV once daily in HIV-1-infected adults, with HIV-1 RNA<50c/mL (VL<50c/mL) for at least 12 months and no history of virologic failure. Participants (pts) were randomized 1:1 (stratified by baseline 3rd agent class; age.

Results: 1024 pts were randomized and exposed (DTG+RPV 513; CAR 511), across both studies. Switching to DTG+RPV was non-inferior to continuing CAR at Wk48 for VL<50c/mL in pooled analysis of both the ITTe population [95% vs. 95%; difference: -0.4% (95% CI: -3.1%, 2.3%)] and the per-protocol population [96% vs. 96%; difference: 0.7% (95% CI: -3.3%, 1.8%)]. Efficacy results for SWORD-1 (VL<50c/mL in ITTe [95% vs. 96%; difference: -0.6% (95% CI: -4.3%, 3.0%)]) and SWORD-2 (VL<50c/mL in ITTe [94% vs. 95%;

difference: -0.2% (95% CI: -4.2%, 3.8%)]) were comparable. Low rates of snapshot virologic failures (VFs) at Wk48 were observed for both studies (Table 1). One pt on DTG+RPV with protocol defined VF had an NNRTI RAM (K101K/E); no pts had any INI RAMs. More adverse events (AEs) were reported and led to discontinuation in the DTG+RPV arm; no unexpected AEs were identified for either drug.

Conclusion: A switch to a novel, once daily 2DR of DTG+RPV demonstrated high efficacy and was non-inferior to the continuation of CAR in virologically suppressed HIV-1-infected adults. The safety profiles of both DTG and RPV were consistent with the respective labels. A DTG+RPV 2DR offers the potential for reduction in cumulative ART exposure, without an increased risk of virologic failure.

 

 

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Comment: See abstract below.

This phase II study presents non-inferior results and several bictegravir phase III trials in both naïve and switch patients are underway in Australia and abroad. Its great to see a study comparing a new agent to DTG, essentially the gold standard integrase inhibitor at present. 

Bictegravir represents a potentially exciting addition to the integrase inhibitor family-  a once daily, un-boosted medication with a high genetic barrier to resistance. It shares the same limitations as dolutegravir in terms of interaction with polyvalent cations and metformin boosting.

If all goes well, it will be co-formulated with F/TAF as a single pill regimen. Given its high barrier to resistance and absence of ABC, such a regimen may become an ideal option when initiating HAART in the absence of a resistance genotype/HLA-B*5701 result (eg in acute HIV infection or resource limited settings) or in individuals with high cardiovascular risk.

 

41 RANDOMIZED TRIAL OF BICTEGRAVIR OR DOLUTEGRAVIR WITH FTC/TAF FOR INITIAL HIV THERAPY

Paul E. Sax et al

Background: Bictegravir (BIC, GS-9883) is a novel, unboosted, once-daily INSTI that demonstrated potent activity in a 10-day monotherapy study and has in vitro activity against most INSTI-resistant viruses.

Methods: Treatment naive, HIV-infected adults randomized 2:1 to receive blinded treatment once daily with BIC 75 mg or dolutegravir (DTG) 50 mg; both were given with open label emtricitabine 200 mg/tenofovir alafenamide 25 mg (FTC/TAF). Treatments were administered without regard for food for 48 weeks. The primary endpoint was the proportion with HIV RNA <50 copies/mL (c/mL) at Week (W) 24 using snapshot analysis. Noninferiority was assessed through 95% confidence intervals (CI) at W24 and W48. Safety

(adverse events [AEs] and laboratory results through Week 48) was a secondary endpoint.

Results: Of 98 patients enrolled, 65 were randomized to BIC+FTC/TAF and 33 to DTG+FTC/TAF. Baseline characteristics were balanced between arms. Virologic success (HIV-1 RNA <50 c/mL) at W24 was 97% for the BIC arm and 94% for the DTG arm, and at W48 was 97% and 91%, respectively. One subject in the DTG arm had HIV-1 RNA >50 c/mL at W48. No viral resistance was detected in the BIC+FTC/TAF arm. Mean CD4 count increases at W48 were 258 cells/μL in the BIC arm and 192 cells/μL in the DTG arm. There were no treatment-related serious adverse events and no deaths. The most commonly reported adverse events were diarrhea (12% in each arm) and nausea (8% BIC, 12% DTG). One subject in the BIC arm discontinued due to an adverse event of urticaria following the W24 visit. Median changes in estimated glomerular filtration by Cockcroft-Gault (GFRCG) at W48 were -7.0 mL/min for BIC and -11.3 mL/min for DTG, with no discontinuations due to renal adverse events.

Conclusion: Bictegravir+FTC/TAF and DTG+FTC/TAF both demonstrated high virologic response rates at both W24 and W48. No treatment-emergent resistance was detected in the BIC+FTC/TAF arm through W48. Both treatments were well tolerated, and no significant safety signal was detected in either arm. Estimated GFR changes were consistent with known inhibition of tubular creatinine transport by BIC and DTG.

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