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 doesn’t 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 4.1–7.2, 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.

 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 that’s been discussed for decades. We’re 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 I’ll end with Jean Michel’s 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 Kaplan–Meier 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.

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.

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.

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.

Comment: Abstract follows:

This study demonstrates non-inferiority of treatment switch to dolutegravir/rilpivirine at 48 weeks versus remaining on current antiretroviral therapy. It’s 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, it’s 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. Dolutegravir’s (DTG) potency, safety and resistance barrier make it an optimal core agent for 2DR. Rilpivirine’s (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.

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. It’s 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.