Roy Gulick, from the Division of Infectious Diseases, Weill Cornell Medical College, New York City, gave answers to the question "What next for ARVs?" during his presentation today.

But before we talk about the future, let's pause and look at ART in the year 2016:

• When to start:
• All international guidelines now recommend the start of ART at the time of diagnosis, irrespective of CD4 counts
• For details of these guidelines, visit the following links:
• US DHHS 2016
  
• IAS-USA 2016
• EACS 2016
• UK 2016
• WHO 2016
• Currently 29 approved drugs:
• From five broad mechanistic classes:
• EI, NRTI, NNRTI, PI & INSTI
• We currently have up to 10 recommended first-line regimens:
• 1 standard strategy: 2 NRTI + [NNRTI, PI or INSTI]
• Properties of ART:
• Virologic activity
• Safety and tolerability
• Convenience
• Access and cost
• Life expectancy

 

Newer strategies, formulations and investigational ARV agents:

• Long acting compounds under investigation:
• Injectable formulation of the NNRTI, Rilpivirine LA (long acting)
• Injectable formulation of a new INSTI, Cabotegravir
• Formulations of implantable devices that provide sustained release of ARVs
• A new NNRTI, Doravirine (DOR):
• Active agains drug-resistant strains
• In vitro active against viral strains with K103N, Y181C, G190A, E101K, E138K or K103N/Y181C
• A new INSTI, Bictegravir:
• In vitro active agains viral strains with integrase resistance
• Two new mechanistic classes under investigation and in clinical development:
• An oral CD4 attachement inhibitor, BMS-663068:
• BMS-663068 is a prodrug of BMS-626529 an inhibits CD4 binding to gp120 
• HIV maturation inhibitor (MI), BMS-955176:
• Binds tightly to HIV GAG
• In vitro active agains strains with polymorphisms and PI resistance

There has also been a lot of talk at the conference about two-drug regimens and Dolutegravir monotherapy, but until we have conclusive data to support the efficacy, three-drug regimens remain the current gold standard.

Conclusion:

Currently, we can control HIV infection long-term with potent, safe and convenient ART that leads to prolonged healthy survival in our patients. The development of newer drugs and new drug classes opens up options for patients with multiple resistances. 

Andri Rauch, Bern University Hospital and University of Bern, Switzerland presented on the achievements and remaining challenges of Hepatitis C treatment.

We have all been fortunate to witness the breakthrough in HCV treatment from interferon-based regimens to DAAs:

• Interferon acts by unspecific activation of innate and adaptive immune responses.
• DAAs are specific and highly efficient in inhibition of the HCV life cycle.

The improvements in treatment efficacy in SVR genotype 1 infection:

• by HIV status:
• HCV SVR (cure) in both HIV/HCV co-infected, as well as HCV-monoinfected patients used to range from ~40% clearance in HIV/HCV co-infected patients to ~50% in HCV-monoinfected patients using PegIFN/RBV alone
• Treatment with DAAs are now showing cure rates over 90% (and in some cases even up to 100%) in BOTH the co-infected and monoinfected patient
• by cirrhosis status:
• Cure rates of just over 30% have been observed in patients with cirrhosis who underwent treatment with PegIFN/RBV alone. The numbers were slightly better for patients with no cirrhosis at ~50% SVR on the PegIFN/RBV regimen
• Treatment with DAAs are showing cure rates of ~95% and over.
• by IL28B status:
• SVR in IL28B risk allele were ~30% when PegIFN/RBV was used, compared to ~75% in IL28B protective allele carriers on the same regemine
• Again, different DAA combinations show cure rates very close to 100%

Thus, DAAs achieve high cure rates irrespective of host and viral characteristics.

Changing from complex to simple treatments resulted a few (very welcomed) changes within the past 5 years:

• Single tablet regimens
• Treatment durations of 8; 12 or 24 weeks (depending on HCV genotype, cirrhosis status and past DAA failure)
• No requirement for response-guided decisions
• Minimal monitoring required

Andri discussed the remaining challenges:

1. Difficult to treat: cirrhosis, NS5A RAS, GT3
• lower SVR in GT3, cirrhotics and those with NS5A RAS
2. Difficult to treat: renal impairment eGFR <30mL/min or haemodialysis
• Suggested options for GT 1 and 4:
• ombitasvir/paritaprevir/r +/- dasabuvir
• grazoprevir/elbasvir
• Other genotypes:
• use sofosbuvir-based regimens with caution
• close monitoring of renal function
3. Drug-drug interactions:
• especially with HIV ART
• make use of the Liverpool HEP Drug interactions website
4. Events after SVR if therapy is started too late:
• clinical improvement moderate in patients with decompensated cirrhosis with SVR
• SVR does not eliminate risk of HCC
• deferring treatment increases risk of liver-related events:
• persistent metabolic risk factors
• co-infections
• liver toxicity due to drugs alcohol or co-medication
• genetic predisposition to accelerated liver fibrosis
• reversion of liver fibrosis/cirrhosis is frequent but not universal
5. New epidemics and reinfections
6. The cascade of care: comparing HCV with HIV (following the 90:90:90 targets). Increase of treatment rates to reduce prevalence by 90% in 2030.
7. Affordability and reimbursement restrictions
• Due to cost the DAAs are not readily available in many countries
• The costs of treating all patients with hepatitis C would be equal to at least a tenth of the current annual cost for all medicines.
8. Treatment-as-prevention and risk behaviour
• Stabilisation in high-risk behaviour combined with an increase in treatment uptake is required to curb the HCV epidemic among HIV-infected MSM.
• If this can be achieved, treatment-as-prevention can reach to HWO elimination targets (90% reduction in new cases by 2013)

In summary:

Goals of HCV therapy: achievements and challanges.

• Cure HCV infection
• Minimise adverse events
• Provide universal access to therapy
• Prevent HCV transmissions

 

Christian Callebaut, Clinical Virology, Gilead USA, presented the findings of their clinical trial GS-US-292-0119.

Virologically suppressed, treatment-experienced patients on complex multi-tablet regimens were randomised to either switch to a simpler, more convenient antiretroviral regimen or remain on their current optimised ART.

After 48 weeks:

• The regimen consisting of E/C/F/TAF DRV demonstrated maintained viral suppression in 94.4% of patients.
• In the DRV-containing “Stay on Baseline Regimen” arm, maintained viral suppression was 76.1%

All patients had documented resistance to 2 classes of antiretroviral (ARV) agents at baseline. Detailed ARV regimens and the resistance profile of the study population are described.

Study methods:

The Stanford HIVdb algorithm version 8.01 was used to calculate genotypic susceptibility scores (GSS).

For each drug, a 5-point scale was used:

• Susceptible = 1
• Potential low-level resistance = 0.75
• Low-level resistance = 0.5
• Intermediate-level resistance = 0.25
• High-level resistance = 0

 The total GSS for a given regimen was calculated as the sum of the scores for each individual drug. 

Results:

A total of 94.8% had documented resistance to 2 classes of ARVs, including:

• protease inhibitors: 34.8%
• non-nucleoside RT inhibitors: 88.1% and
• NRTIs 94.8%.

The most common resistance associated mutations (RAMs) were:

• Protease Inhibitor RAMs: L90M (15.6%) and V82A/F/L/S/T (14.8%).
• NNRTI-RAMs: K103N/S (63%) and Y181C/I/V (19.3%) and
• NRTI-RAMs: M184V/I (83%) and K65R (23.7%).

Thymidine analog mutations (TAMs) were present in 42.2% of patients (59.6% with one or two TAMs and 40.4% with three TAMs). 

The distribution of GSS at study entry was similar across treatment groups.

Patients in the E/C/F/TAF DRV arm maintained virologic suppression similarly, regardless of the DRV dosage received before switching (33/33 and 51/56 with treatment success in the 600 mg BID and 800 mg QD groups, respectively).

In the E/C/F/TAF DRV arm,

• 11/89 patients (12.4%) had GSS <2,
• 51/89 patients (57.3%) had GSS ≥2 and <3, and
• 27/89 patients (30.3%) had GSS ≥3.

Within each treatment group, patients maintained virologic suppression similarly regardless of their GSS at study entry.
 

Conclusions:

• Despite the high incidence of pre-existing resistance in this population, including resistance to ≥2 classes of ARV agents and presence of K65R or ≤3 TAMs, strategic simplification to E/C/F/TAF DRV was statistically superior to staying on the baseline regimen.
• Patients benefited from switching regimen regardless of their prior DRV dose and their GSS.
• Treatment with E/C/F/TAF DRV offers a simpler and more convenient option for treatment-experienced patients on complex multi-tablet regimens.

Details of the study can be found here: https://clinicaltrials.gov/ct2/show/study/NCT01968551

 

 

 

 

Anthony Fauci from the National Institute of Allergy and Infectious Diseases (NIAID) & National Institute of Health (NIH), Bethesda, USA, presented an excellent keynote lecture on ending the HIV/AIDS pandemic.

He started by taking us through a timeline of HIV infection. Starting in the 1980s, when the mean life expectancy of a newly diagnosed 20 year old (not on ART) was ~12 years. We followed the science through time and today, over 35 years later, the mean life expectancy of a newly diagnosed 20 year old (on ART) is ~53 years.

What we've learned since the 1980's regarding the etiology, virology, pathogenesis, treatment and prevention have given us a better understanding on how all these advances should continue to be used in conjunction in order to end the HIV/AIDS epidemic.

We've discussed treatment as prevention (TasP) and looked at a traid of pivotal ART studies regarding the treatment of individuals with HIV infection:

• The SMART study showed that episodic ART is inferior to continuous ART
• The HPTN 052 study showed that early ART reduces HIV transmission to uninfected sexual partners by 93%
• The START study showed that early ART reduces serious illness or death by 57%

 

We are all aware of the continuum of care when our patients have a positive HIV test results, but we should also be very proactive in the continuum of prevention in those who test negative.

Despite our 90/90/90 targets, the numbers of newly diagnosed HIV infection have plateaued globally since 2009.

Continuing to improve access to ART and HIV prevention strategies, such as pre-exposure prophylaxis (PrEP) could dramatically decrease HIV-related deaths and the rate of new HIV infections.

The efficacy of PrEP has been proven in multiple studies and most recently the San Francisco Strut PrEP program showed no new HIV infections in >1200 men on PrEP in nurse-lead intervention over nearly 1.5 years. There were 82 new infection at that clinic among men not enrolled in the PrEP program.

The two main remaining scientific challenges for HIV identified are:

• Addressing HIV persistence
• eradicate the reservoir - classic "cure"
• control viral rebound - sustained virologic remission
• Development of a safe and effective preventative HIV vaccine 

Towards a HIV vaccine:

• The first signal of efficacy (31%) in a HIV vaccine clinical trail - RV144, was seen in: Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. S Rerks-Ngarm, et al. For the MOPH-TAVEG investigators. N Engl J Med 2009; 361:2209-2220. Dec 3, 2009
• Additional work since this study has lead to a large-scale HIV vaccine trial that will launch in November 2016 in South Africa: HVTN 702 modifeid RV144 prime-boost regime
• More work is also being done on Neutrolising Monoclonal Antibodies, discovered since 2009.

 

Conclusion:

Treatment + non-vaccine prevention + vaccine = durable end of the HIV/AIDS pandemic