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Practical Guide SAFE 4/7

Practical Guide SAFE 4/7


This paper was originally published here, in French. We provide the google translation for your convenience. Proper translation will come soon. Some practical aspects may differ where you live.


The latest version can be downloaded from the full reference file: www.tinyurl.com/maliberte v 1.05 September 2015: Following the publication of ANRS-4D, this guide is being revised; new version expected in September 2016

SAFE GUIDE 4/7 (According ICCARRE and ANRS-4D)



ANRS-4D revolutionizes short cycle 2016 release differs from the version 2015

A - Am I an eligible patient?
    Undetectable and VL <50, confirmed, more than 1 year under the same effective TRI = OK
    My lower CD4 (Nadir)> 4 = OK; previous AIDS = OK; See FAQ # 5
    Recent CD4 <200: consider intensification or wait six months
    History of resistance, or non-adherence: caution or consider alternative
    If eligible, see Premium eligibility (Genotype): advantage = Direct to 4/7
B- Am I eligible under treatment?
    Any TRI (including Eviplera ®) = OK; TRItherapy only (single combo, booster = OK)
    Yet ... Triumeq ™, Tivicay ™: on-going trials, therefore, see Dr. and forums ...
    Stribild ™ / ® Genvoya ®: so complex Caution + Dr + monthly CV
C- Schedule:
    Step 1: 1 year VL <50 (2 successive undetectable VL) and 100% adherence
    We will skip entire days. A day whare dose is skipped, nothing is taken
    Blood tests on Monday, before resuming meds (standard dosages)
    If eligible Premium: you can skip step 2 and 3, go direct to 4/7
    Step 2: At the beginning we skip ARVs (and all ARVs) on Sunday,
    and Sunday only (6/7)
(do not see your doctor at every VL ...)
    VL-month 1, VL-month 2, VL-month-4, VL-month-6 (and so on).
    Step 3: Then you jump Sat (5/7) (consecutive days!)..
    VL-month 1, VL-month 2, VL-month-4, VL-month-6 (and so on).
    Step 4: Skip Friday Saturday Sunday (4/7)
    VL-month 1, VL-month 2, VL-month-4, VL-month-6 (and so on).
    Step 5: stabilize at 4/7: Dr once / year; Pharmacy 2 / year; VL 4-6 / year
D- medical assistance:
    Desirable, but, above all, VL monitoring (higher frequency) is essential
    If no medical support, biological monitoring remains a must-do (unless Premium eligible)
    If VL raises, and not a blip, (never happened ...): see Dr Asap
    If this schedule is uncomfortable or poor adherence: go back to 7/7 or
    See alternative relief (Bi or Mono-Tivicay®) without mixing strategies
    Stock / surplus: consider generics and donate to PreP
E- Share:
    Your experience with VL, fellings, doctor, stock, adverse effects
    Forums: = OK; give this Guide to Physician = OK
    Premium (ANRS-4D) facilitates entry into the short cycle: Enjoy!
    FAQ: see below

This practical guide is a base for reflection, in no case a medical advice
scientific file to download here www.tinyurl.com/maliberte

Good to know: If fully eligible Premium: no need to close the CV. In France not need a prescription to make a CV


Frequently Asked Questions



In the order of +/- Memento ... (FaQ always being improved)
List of Questions followed answers:

How does the 2016 version differs from the 2015 version ?
Which trials and studies validate the short cycle reduction strategy
Am I an eligible patient? Why ask this question first?
If eligible, see Premium eligibility (Genotype)
Anyone with confirmed VL <50 (undetectable)... What does this mean ?
More than 1 year under the same effective TRI = OK ... What does this means
My lowest CD4 (Nadir)> 4 = OK; Prior AIDS = OK!
Recent CD4 <200: intensification or wait 6 months: When to start?
What CD4 level before you start the short cycle?
Is age a criterion?
Non-adherence: prudence or think alternative: The Short Cycle is demanding!
The alarm and the pill scheduler:
I am eligible, but my doctor says no: Demand an explanation!
I want to have children: am I eligible?
I am eligible: is it valid for any schedule: 4/7, 5/7 or 6/7?
Here, eligibility conditions (patient) are less restictive than for the ANRS-4D trial
What is the Premium eligibility (ANRS-4D)? What are the advantages?
Any TRItherapy = OK ... What does this mean?
TRI therapy only ? ... Please explain ...
Single pill combo (STR), boost = OK ... Please explain ...
Which are untested triple therapies?
Special case: Eviplera ® (aka Complera ®)
Special case: Stribild ® / Genvoya®
Special case: Tivicay® and Triumeq®
Special case: Viramune ® (nevirapine)
Special case: Efavirenz (Sustiva ® / Atripla)
Efficiency and Adherence
Take the meds (usual dosages)
When to start the Short Cycle
On days OFF, you take nothing
Blood tests before resuming meds
Take your medication at the usual time
The medical analysis lab is closed this Monday what should I do?
VL-month 1, VL-month 2, VL-month 4, VL-month 6: why frequent VL?
The trials validate 5/7 and 4/7 strategies : Why do frequent VL, as in the trials?
Am I at risk of viral rebound?
If eligible Premium: you can skip step 2 and 3, direct 4/7
Why a stepstone at 6/7?
The first vL at month 1: Why?
My doctor gives me a VL prescription every 6 months
How much will more frequent VL cost?
For viral load, hospital laboratory or downtown Lab?
VL without prescription ... The assistant is surprised, what to say?
VL without a prescription, at 60 Euros, this is too expensive for me
There are no additionnal doctor visits
I want to make the vaccine against seasonal influenza. How to manage ?
Consecutive days: Why?
The plateau lasts six months: Can I do less?
The last six months tray: Can I do more?
From 5/7 to 4/7 there a risk?
Stabilize 4/7: why not go to 3/7?
View 1 doctor once a year ...
Go to the pharmacy 2 times a year ...
Go to Lab 4 to 6 times per year
In total ICCARRE is less interaction with healthcare professionals ...
Medical monitoring: desirable but can do without it if necessary
Biological monitoring (CV close) essential
What if CV ascent?
When to confirmation CV (resume after a rise to> 50)?
What is a blip?
I have a lift CV and this is not a blip, what to do?

How does the 2016 version differs from the 2015 version ?

ANRS-4D revolutionizes the short cycle; 2016 release differs from the 2015 release:
- Eviplera® (aka Complera ®)is now tested: 100% success
- Premium Eligibility: a novelty that makes the short cycle even more attractive
- Under Premium eligibility condition, Direct transition to 4/7 is validated
- With strictly eligible and strictly adherant patients, VL has never increased: in this context, our high frequency blood draw rule can reasonably be ignored.

Which trials and studies validate the short cycle reduction strategy

There are five published trials and 1 in progress: they are all conclusive in favor of short cycle

FOTO: clinical study (published in February 2007): 30 patients (10 under EFV, 10 NVP, 10 with PIs): no virologic failure with EFV, rare rebounds virological NVP and PIs, and always virologic ressuppression upon return to 7/7, with no change of triple therapy. Safe for patients on EFV and NVP, the strategy has proved durable (> 3 years). The original documents can be found at tinyurl.com/CHE-FOTO

FAUCY: randomized trial with 57 patients in the arm 5/7 and 57 in the arm 7/7: the 5/7 arm is superior in terms of viral suppression and reduced toxicity. use of Efavirenz + 2 NRTIs. The original (April 2010) documents can be found at tinyurl.com/CHE-FAUCY

ICCARRE 1 & 2 clinical study in Garches (AP-HP), published in two parts: the first 48 patients (Faseb: June 2010) completed to a total of 94 patients (Faseb April 2015). Concludes that 100% success in 4/7 (on the many cART studied, including Isentress ® (RAL) based). Features an exploratory part: 3/7 ... 1/7 schedules. The important point is "100% success in 4/7"; The 2 publications are available tinyurl.com/CHE-FASEB2.

BREATHER: The largest randomized trial with 99 patients in the 5/7 arm and 100 in the 7/7 arm: 5/7 arm is slightly better in terms of viral suppression and reduced toxicity. Efavirenz + 2 NRTIs. Children 8 to 24 years of which 25% are adults. The original presentation (February 2015) is available tinyurl.com/CHE-BREATHER

ANRS-162-4D: Trial completed and published in 2016, inspired by ICCARRE. It is multicenter, nonrandomized, testing the effectiveness of a direct transition from 7/7 to 4/7 under active antiretroviral therapy. Results have been published on 07.19.2016 at Durban. ANRS-4D validates independently results reported by ICCARRE 1 and 2. Eviplera ® (aka Complera ®) is included, with total success. INIs are not tested.

ANRS-Quatuor: Trial under definition: This is has a twofold aim: one is to register the 4/7 in administrative regulations. So you may want to enjoy the freedom of the window of opportunity, in order to stock before any draconian obligation prevents you from doing so. The other aim is to test integrase inhibitors (eg Triumeq®)

Am I an eligible patient? Why ask this question first?

This is the very first question; we do not know if it determines success, it is thought that certain conditions specific to the patient's history, invite to consider other strategies than the short cycle reduction. If the answer is clearly negative, it is better to try an attractive alternative rather than waste energy. If the answer is 'gray', we be cautious. That's the only question that can, from the outset, a priori, exclude a patient from the short cycle strategy: you must consider it honestly.

If eligible, see Premium eligibility (genotype)

Eligible patients can check if they are eligible for one additional requirement, introduced with the ANRS-162-4D trial. This additional requirement is an audit done before initiating the short cycle, on the genotype (also called resistance test). This condition is not necessary to be eligible at large. It entitles to 2 'privileges': switch to 4/7 direct and rid of frequent VL. That's a condition that crosses patient's own eligibility (the virus) and a drug eligibility. Does the Premium eligibility create a privileged class, a 'first' class? Perhaps, but the benefits are such that we can not hide them. Does Premium eligibility create a dependance to the medical profession? Not really. Simple eligibility will be enough for patients unwilling to enter the subordination.

Anyone undetectable, with confirmed VL <50 (undetectable) ... What does this mean ?

Undetectability, which is defined as a viral load below the instrument detection limit (typically 20, 40 or 50, depending) is a prerequisite. (Undetectable this is a requirement, and let's make it clear undetectable: a detectable VL, and quantified at 45 <50, but detectable, therefore not eligible). You should see a < on your analysis sheet. The undetectable is not enough: it must be confirmed by a subsequent VL (typically six months apart). Once undetectability is first reached, with the induction combination therapy, in rigorous 7/7 mode, it is possible, rare, but possible, that undetectability is lost (still under 7/7) some time later. If confirmed by a second (or even third) follow-up VL (typically six months apart), then one is sure of its effectiveness! Typically one does not enter the short cycle schedule before 18 (better: 24) months from initiation (or change) of treatment. In case of a change of HAART, it is recommended to patiently wait, in order to thoroughly check its effectiveness. This program is open to the vast majority of patients, and all triple therapy; in return, it is very conservative in terms of planning: the patient has a lifetime of treatment ahead, there is no hurry ... This waiting time also allows viremia to go down from 20 to typically 1 or 3- 4, this descent, called Phase III, is slow because it corresponds to the elimination of CD4 infected lymphocytes, that are slower to disappear than others, and whose half life is several (10) months. For more details see the question: When to start?

More than 1 year under the same effective TRI = OK ... What does this means ?

One should ensure that the combination therapy which will be made ligher ( 6/7, 5/7 and 4/7 ) is effective, really effective. Of course, you must have a confirmed undetectability. In the event of significant change in therapy, you must re-check the effectiveness of the new therapy by a confirmed undetectability, twice, in the same fashion: 7/7. Example of significant therapy change: moving from dual therapy (eg RAL + NVP) to triple therapy single pill (eg Stribild®.). Insignificant change example: repackaging of the same molecules in a single tablet (Sustiva ® + Truvada becomes Atripla ®) or, conversely, the 'split' of a combo single pill to opt to generic. Substitution of Emtricitabine (FTC, that is to say of the fluorinated Lamivudine) by Lamivudine (3TC) (or vice -versa) is not significant, but there is no hurry and a simple confirmation by giving it 6 months of observation, should be considered.

My lowest CD4 (Nadir)> 4 = OK; Prior AIDS = OK!

Looking at the six clinical trials: there has never been a NADIR-based exclusion condition.
In ICCARRE, the lowest Nadir (that is to say, the lowest level of CD4 ever measured) was 5. In addition, 63% had either declared an AIDS or had a CD4 count <200 (an AIDS designation in the former nomenclature CDC). There is no reason to make it a cause of exclusion. A patient should never be opposed this argument: there would be no basis. This program is open to all; in return, it is very careful about checking efficiency, undetectability, slow progression, higer frequency VLs.
Nadir <200 or prior AIDS Grade C is not a priori exclusion condition.

The current use of PIs (protease inhibitors) is not an a priori exclusion condition.

The combination of the two above situations ((Nadir <200 and / or previous AIDS grade C) combined with the use of IP) could be unfavorable ... This is not known for sure. In such a case, it is appropriate to consider switching to a NNRTI or Dolutegravir based regimen before entering the short cycle.

Patients with a history of AIDS or low CD4 are invited to follow closely the conservative recommendations in this guide.

Recent CD4 <200: intensification or wait 6 months: When to start?

This is discussed below and also here

What CD4 level before you start the short cycle?

The maintenance of virologic success is central to the strategy: if is enough for good immune reconstitution. Clinical trials invite to wait for 1 year of undetectability, or more, and have CD4> 200 (the lowest seems to be in the FAUCY test to 219, see table 1 of FAUCY test). So typically 18-24 months from the start of treatment. Leibowitch, in Garches, has a success rate of 100%: he is very patient at this stage there ... After 2 years, the patient gets an idea of ​​what will be its reconstitution (say, his return to > 200): if progress is continuous, why not wait? If progress is capped below 200, a change in treatment or temporary intensification (eg. Adding Maraviroc ® or Isentress ®), sometimes does the trick. CD4 increase at their own pace and do as they want ... Intensification, or change of treatment are generally disappointing, but it seems to work for some patients, it is appropriate to consider (as part of a relief project or not ...). This therefore takes us to 30-36 months after initiation: with modern, effective treatment, if it does not come after optimization of the treatment, this then means that the constraint lies elsewhere ... And over-medication will not change anything ... We can, therefore, after optimizing and waiting more than usual, move forward a lower medication burden, very gradually and very carefully. Note that the short cycle trials show no loss of efficacy on immune reconstitution due to the short cycle strategy.

Is age a criterion?

Apparently, no ... The youngest participant, at baseline, was 8 (BREATHER trial) and the oldest 84 years (ICCARRE) at baseline. in the BREATHER trial, mostly children, there was actually one quarter of young adults (approx. 25). No lack of efficiency has never been found, therefore, no lack of efficiency linked to age: age does not seem to be a legitimate exclusion criterion. Remember that various studies show better compliance in patients > 50 years old.

Non-adherence: prudence or think alternative: The Short Cycle is demanding!

You know that you will be able to rest during the weekend: that should be enough to motivate you! The short cycle users post the highest level of adherence. Adherence-challenged Patients, unable to stick to a regular and demanding pattern, for any reason whatsoever, should stay away from this strategy: for them, it is not suitable! There are alternative strategies to consider (eg. Dual therapy NNRTI + INI), but in any case, the short-cycle strategy is not for hooky players!

The alarm and the pill scheduler:

These are 2 useful tools. A doctor who accompanies a patient or investigator overseeing a trial must ensure their proper use. In this era of smartphones, annexes of our brain, we we can't live without them, load an app, take a picture, use a pillbox, picture before and after, upload to Instagram and voila! Everyone uses the means as s/he sees fit, but must be sure of excellent adherance!

I am eligible, but my doctor says no: Demand an explanation!

You can trust a doctor trained in the short cycle techniques (see our list of best doctors). they are very rare. The patient is entitled to demand an explanation. Some are ledgit (eg. HBV, HCV requiring treatment, ...). Demand a written notice. Otherwise, send a registered letter to your doctor, recalling the objections and ask for a second opinion, typically from a hospital ward with enough experience: (In France, that would be APHP in Garches). A registered letter and a copy to the hospital can be helpful if you consider participating in legal actions that are sure to bloom, one day, for over-medication and poisoning.

I want to have children: am I eligible?

Among Garches patients (10 pregnancies) and BREATHER (5 pregnancies) there has been not a single case of contamination of the partner nor the baby. Nothing indicates that the conception, by natural means, under intermittent treatment in short cycle, presents a risk. Note that protecting the fetus, the unborn child, from overexposure to ARVs may be a legitimate reason to be interested in short cycle ... You may want reassurance by monitoring the Viral Load more often. Except for APHP in Garches No hospital has published experience in this area: it is, for now, where you will get the most educated opinion. Information can be obtained from there. Do not decide alone.

I am eligible: is it valid for any schedule: 4/7, 5/7 or 6/7?

The patient's eligibility (and history with the virus) is as valid for 6/7 as for 4/7. The patient's eligibility is the criterion to consider in the first place. If you pass this hurdle then you go to to the following question: the eligibility of the treatment. If you are eligible, then also check the genotype efficacy of your current meds, you might also be 'Premium', which comes with many advantages.

Here, eligibility conditions (patient) are less restictive than for the ANRS-4D trial

That's right. Most patients meet the ANRS-4D eligibility criteria. It is recomanded to learn about them: they are in full here or file. For the 4D trial, limited to 100 patients, it was important to select patients representative of the majority of patients. Here, the eligibility requirements are wider, because other trials were more open. In return ... escalation is slower (6/7 then 5/7 then 4/7, while 4D allows to go direct to 4/7) and the requirement of adherence and frequent VL are emphasized. 4D requires 3 VL (6 months, apart) and the same ART for at least 4 months. This is stricter than other trials ... Here, we request 2 undetectable VL, recommending 3; but the passage by 6/7 gives time to time.

What is the Premium eligibility (ANRS-4D)? What are the advantages?

The Premium eligibility conditions (ANRS-4D) are available here or here. The main difference is in the efficiency verification. ANRS-4D requires a drug efficacy diagnostic based on Genotype (also called resistance test): At least one genotype (amino acid sequence of the reverse transcriptase and / or protease according molecules being used) must be available in the patient's history; the virus must be sensitive to all current antiretroviral drugs, on all available genotypes.

Genotype is routinely performed in France. The patient sometimes does not have a copy. It is still possible (but no fun) to do it again. If we have the document, we can ask a specialist to validate the condition of inclusion. Otherwise, ask Dr. De Truchis (Garches) to do the evaluation. This service, by simple e-mail is free.

This condition is more restrictive and opens to additional benefits: The ANRS-4D showed a 100% success in fully eligible and fully compliant patients. The protocol calls for direct reduction from 7/7 to 4/7. The trial monitoring imposed frequent VL. In these patients, there was no significant rise in the VL. Not a single one, therefore, frequent VL monitoring appears useless: no need for additional prescriptions n for blood draws other than usual.

conditions Simple Eligibility Premium Eligibility
a priori efficiency validation No Yes (genotype required)
validation of usage efficacy
 
2 successives UD VL
 
3 times VL < 50
(make sure it is undetectable)
minimal duration of current ART 12 months 4 months
Advantages
 
no Genotype
 
4/7 direct
frequent VL unnecessary?
disadvantages 6/7, 5/7; frequent VL Genotype required or redone


Any TRItherapy = OK ... What does this mean?

Any 'classic' Triple therapy that has been used in trials. Some molecules are equivalant to each other, so, many therapies are infact eligible... Some of the latest were not tested (see below untested TRI). Eligible combinaisons should be part of those approved for First line treatment. These include combinations of 1 x NNRTIs (EFV, NVP, ETV) + 2INTIs (TDF / FTC, ABC / 3TC, AZT / 3TC) or 1 (boosted) PI + 2 NRTIs (TDF / FTC, ABC / 3TC, AZT / 3TC) or Raltegravir (Isentress ®) + 2 NRTIs (TDF / FTC, ABC / 3TC, AZT / 3TC). List (not exhaustive) (for Combivir ®, consider as equivalent to Truvada ®, for the present purpose):


Complera® (aka Eviplera ®) ; Edurant ® (Rilpivirine) + Kivexa ® ; Atripla ® ; Sustiva ® (Stocrin ®) + Kivexa ® ; Sustiva ® (Stocrin ®) + Truvada® ; Efavirenz (generic) + Kivexa ® ; Efavirenz (generic) + Truvada® ; Efavirenz (generic) + Viread ® + Lamivudine ; Efavirenz (generic) + Ziagen ® + Lamivudine ; Viramune ® + Kivexa ® ; Viramune ® + Truvada® ; Nevirapine (generic) + Kivexa ® ; Nevirapine (generic) + Truvada® ; Nevirapine (generic) + Viread ® + Lamivudine ; Nevirapine (generic) + Ziagen ® + Lamivudine ; Intelence ® + Kivexa ; Intelence ® + Truvada® ; Kaletra ® + Kivexa ® ; Kaletra ® + Truvada® ; Reyataz ® + Kivexa ® ; Reyataz ® + Truvada® ; Prezista ® + Kivexa ® ; Prezista ® + Truvada® ; Isentress ® + Kivexa ® ; Isentress ® + Truvada®
(Note: you can substitute Truvada with Viread + Lamivudine (Generic) and you substitute Kivexa ® by Ziagen® + Lamivudine (Ge)( Ge = generic, see SAFE-Generics)

Drug List for Premium Eligibility: All the above list except Isentress ®: the integrase inhibitors have not been tested in ANRS-4D (which defines the Premium eligibility). Isentress has been used successfully in ICCARRE-2 (3 patients in progressive mode, simple eligibility)

TRI therapy only ? ... Please explain ...

This excludes monotherapies and bi-therapies (e.g. Rilpivirine + Dolutegravir.) (Ex Kaletra alone.). Boosters (Ritonavir 100 mg or cobicistat) do not count in the calculation. 3 or 2 molecules combined in one tablet are counted as 3 and 2 respectively. only account for the active molecules.

Quadritherapies: the quadrithérapies, built following virological failures are excluded: the patient should consider another strategy, or resign themselves to the situation ... Quadrithérapies built according to APHP Patent (inventor J. Leibowitch; APHP = Paris Hospital Group) in order to go beyond of 4/7 are eligible, provided that the transition to 4 active molecules is not motivated by lack of efficacy, observed in the patient, of the combination of 3 molecules. The possibility of a 4/7 Maintenance with a Tivicay® monotherapy is being explored.

Single pill combo (STR), boost = OK ... Please explain ...

Some triple therapy combinations have been combined in a single tablet (eg. Atripla ®). This is a single pill, but still a combination therapy, so it is valid. Similarly Truvada and Kivexa ® contain each 2 molecules (TDF / FTC and ABC / 3TC, respectively), so they account for 2 ... Some combinations include a booster (hepatic metabolism inhibitor, it slows the elimination by the liver so increases the availability of the molecule): the booster is neutral in the count. An example of valid TRItherapy is Prezista ® (DRV) + 100 mg Norvir ® (RTV) + Truvada (TDF + FTC): it is a TRItherapy. Prezista ® (DRV) + 100 mg Norvir ® (RTV) is sometimes noted DRV / r (small / r indicates the presence of the booster)

Which are untested triple therapies?

Because they are new on the market, they have not been tested yet: These are Stribild ® (EGV / co / TDF / FTC), soon to be replaced by Genvoya ® (EVG / co / TAF / FTC) and more recently Tivicay®, taken in combination with Truvada or Kivexa ®. Tivicay® + Kivexa ® is now available in a combined form: Triumeq ®. Not tested ... There is no formal evidence whether they are eligible or ineligible. In order to enter the short cycle with these medications the patient should take the time to ensure they are effective beforehand. Even if they are recent, modern, do not assume a superior virological efficacy. The patient takes the same provisions as for other drugs: confirm 12 or 18 months of good efficiency. In the SAFE 4/7 proposal, there is no practical difference in biological control escalation between the test method (new drugs) and the routine method (for drugs already tested): So there is no reason to exclude untested medicines proposal SAFE 4/7. The patient has a robust, proven, and should stick to it rigorously. Eviplera ® (Complera ® in the US, RPV / TDF / FTC) has been validated by the ANRS-4D. Premium eligibility is not yet available with Issentress®, Stribild®, Genvoya®, Tivicay® nor Triumeq®.

Special case: Eviplera ® (aka Complera ®)

It has been tested in the ANRS-162-4D trial (2015). On 26 patients: no failure. ANRS-4D is, in this aspect, a real progress for Eviplera ® (aka Complera ®) users. It is already clear that many Eviplera ® (aka Complera ®) patients already follow our proposal SAFE 4/7, often starting at 6/7. The ANRS-4D validates the direct passage to 4/7. Direct or progressive? Both are legitimate. The eligibility conditions are known (ANRS-162-4D); they can be inspiring.

Special case: Stribild ® / Genvoya®

Genvoya ® is expected to replace Stribild ®. Notice of the HAS (Haute Autorité de Santé, 06 November 2013) points out: STRIBILD ® has not shown improved efficiency, has a low genetic barrier to resistance, many drug interactions.

If we follow the opinion of the HAS (May 2016) Genvoya ® should only be considered to replace or Issentress ® or Stribild ®. HAS does not recommand the use of Genvoya® outside this context of historical continuity. Moreover, during the GS-US-236-0102 & 0103 trials there were viremia rebounds after undetectability was first reached. It has thus been lost (with case of emergent resistance). The proposal 4/7 calls to confirm good efficiency with at least 12 to 18 months of continuous undetectability. The recommendation here is more relevant: not derogate

Furthermore, the use of a booster (hepatic metabolism inhibitor) reduced the dose of elvitegravir. At the end of the Sunday break, and thus the resumption of treatment, on Monday, the booster is not in the liver. There is no evidence that the dose of elvitegravir, the first day of resuming treatment, will not be affected.

Special case: Tivicay® and Triumeq®

Triumeq ® is the combination of (DTG / ABC / 3TC); before being offered as a single tablet, this combination was common in the form Tivicay® + Kivexa®. An alternative is Tivicay® + Truvada®. This chapter covers the three forms. Dolutegravir is the latest molecule introduced on the market. It therefore was not tested in Short Cycle Trials. Documents released by the manufacturer show a duration of integrase inhibition 10 times higher than the molecules of the same class (RAL and EVG). Moreover, by the admission of formulators, the 50 mg dose was chosen while 10 mg was clearly sufficient for the vast majority of patients. This superiority on paper, has attracted the attention of investigators/clinicians: a DOMONO test (Tivicay® monotherapy in maintenance) is underway, a DOLU HYPO-trial (Tivicay® maintenance as monotherapy, followed by a passage 1d. every 2 days, then a progression to 1/7) is being held in Toulon. (The documents are in the complete file www.tinyurl.com/maliberte). These factors appear favorable. Here the SAFE 4/7 proposal remains: confirm efficiency, prudent entry in Short Cycle and frequent VL. Tivicay® monotherapy Note: it is now being tried in naïve patients. Will these patients do the 4/7 with mono Tivicay ®? It is possible, may be, we will see ... this is a new molecule, allowing for creative propositions: users of these strategies are invited to share their experience.

Special case: Viramune ® (nevirapine)

Recent guidelines recall that the Nevirapine (Viramune ®) should not be proposed as first line for patients with CD4> 400 (for men) and> 250 (for women). With the newest test-and-treat policy, treatment is often initiated above those thresholds. By mechanical effect, this molecule is proposed less often. We can certainly offer it later. It has some interesting properties: long life, high diffusivity in the tissues, edition of viral RNA. Jacques Leibowitch was used it extensively (to explore the 2/7 and 1/7); it has been studied in FOTO. It is not be tested in ANRS-4D; but the accumulation of patients, in previous studies, makes it eligible.

Consequence of the 2NN study, many patients take 2 tablets of 200 mg at one time. Recently, the molecule is provided by Bohringer as 400 mg extendeded release. During a sequence of 6, 5 or 4j. , for the last intake, Viramune ® LP (aka ER) continues to diffuse for approx. 12h. This is not a problem. On the contrary, when you resume, the Monday morning,it will take 12pm. to diffuse. These are not the conditions of the trials that validate the use of this molecule. As a precautionary measure, you may want to use only the Nevirapine (GS), under the usual conditions, or use Nevirapine (Generic) earlier this week, under the usual conditions, and then use Viramune ® 400 mg LP (aka ER), towards the end of the period.

Special case: Efavirenz (Sustiva ® / Atripla ®)

Efavirenz (sold under the tradename Sustiva ®, and contained in Atripla ®) is the most used molecule in short cycle in relief. we discuss it here as the proposal 4/7 SAFE applies to the usual dosage. However, whether a consequence of a therapeutic dosage or tested, of which ENCORE1 trial is emblematic (Initiation with 400 mg of EFV instead of 600 mg), some patients using this dosage (400 mg instead of 600). 4/7 SAFE proposal calls, however not to mix genres, and it is proposed to stick to the standard dose (600 mg)...

Efficiency and adherence

The three key words of the short-cycle strategy are:

Efficiency, progrssive de-escalation, fraquent VL... The effectiveness must be confirmed by 2 (or 3 or more ...) successive VL (6 months apart), undetectable, <50 copies / mL, always under the same TRItherapy; in case of change of TRI, one should ensure efficacy. The ideal is 18 months of sustained undetectability. Adherence is crucial. It should be flawless in the initial treatment phase. Starting early, or with visible viremia, or imperfect compliance, is a violation of the recommendations of this SAFE proposal 4/7. The ANRS-4D trial highlights the importance of adherence: Patient with poor adherence were identified during the trials: these patients had to leave 4/7 and return to the 7/7. Be observant and steady!

Take medication (usual dosages)

The strategy applies with the usual dosages, those use in first line, 7/7. For example, the usual practice is to take Issentress ® 800 mg / day. : The short cycle strategy is done with the usual dosage. It does not recommand to reduce both the dose and use the short cycle. In rare cases, some patients are allowed to take in a single daily dose, even if it is recommended by 1 dose in the morning, one at night, on the record. If this use is effective (sustained undetectability), nothing indicates that we should not use it: progress with caution in the short cycle by following more closely the stepwise recommendations and frequent VL.

When to start the Short Cycle

This question is divided in 3: When to start reduction with regard to viral load, in terms of the immune recovery (CD4) and scheduled blood draws.

When to start reduction with regard to viral load

In the descriptive 'model', after initiation, viral load decreases very rapidly, then more slowly, then very slowly, finally no longer decreases and remains at the bottom. After achieving undetectability, it continues down (but not measurable); this is the general case, a description with 4-phases. In rare cases, individuals observed during initiation of treatment trials, undetectability is lost, then it comes back or not ... We claimed victory too soon. Then, there is inefficiency and risk of clinical resistance. Both the general case and the few cases of 'misleading' undetectability invite to wait beyond (even far beyond) the only first undetectability check point. We begin typically at 18 months (or better at 24 months ...) after the initiation of effective treatment. In the section 'discussions' justifications will be found. This caution also applies when changing triple therapy.

When to start reduction with regard to immune restoration (CD4)

From how many CD4 do I start short cycle?

The lowest CD4 count at inclusion in all trials (375 patients) was 200. Above this value, there is no reason to bother. After achieving undetectability, immune reconstitution takes place at its own pace. If it progresses a little slow (in view of sustained undetectability), then so be it... Dr. Jacques Leibowitch is the only clinician to publicly express an opinion on the subject: inclusion of patients with 200 CD4 or more regardless of nadir. And if the treatment has achieved and maintained maximum control over HIV - the only undisputed goal of ARVs - for these "non reconstituted CD4 in patients," the prescriber is no longer required to over prescibe.

The thresholds 200, 350 or even 500 are relevant to evaluate risk in the absence of treatment: one can not, strictly speaking, make these 'objectives' or 'targets'. Under effective treatment (VL <50 copies, sustained), even a partial reconstruction seems sufficient and nothing indicates that it is necessary to impose a minimum threshold. The proposal 4/7 SAFE provides a threshold of 200, for information only.

When to start reduction with regards to blood draws

you have waited for the second undetectable VL (or even third VL <50), and here you are ... It's good ... We begin short cycle... Well ... We must plan this because, who says progression 6/7 , 5/7 or 4/7 HP says more fraquent VL. If there is no solution for more frequent VL (see locally if you can do even without a prescription), you must start short cycle 1 month before the next scheduled VL.

your VL (blood draw) schedule is giving you the start signal (see why we do frequent VL) and not the latest VL (undetectable <50) obtained.

Either way, you will need a solution for frequent VL (once every 2 months, at least for 1-2 years).

Premium eligible (= as defined by ANRS-4D) and perfectly adherent patients may consider to skip the frequent VL.

On days OFF, you take nothing

On Days OFF you simply take no ARVs. It is not about taking a pill (ex. Truvada) one day, jumping another (ex. Sustiva ®), then take the other the next day by skipping the first. During the break: No triple therapy.

Blood tests before resuming meds

Have blood draws (viral load), at the end of a OFF cycle, before resuming ON treatment cycle. Typically, it's Monday morning. after a break that ends Sunday, as the last day of break. Then you do the blood test on Monday morning (or afternoon, depending on the usual time taken) and medication is taken at the usual time, after the blood draw. The blood test is therefore at the break between the two phases. In practice Monday is well suited, since it marks the resumption of the work week.

Take medications at the usual time

I usually take my medication in the evening. After my Sunday OFF, I just made my blood test this Monday morning. Do I take medication this morning or do I wait for tonight? ... The short cycle opens OFF time per 24, 48, 72 hours. There is no need to change its usual schedule. To do so would break for 36 hours instead of 48 hours. Doing so during a clinical trial would be cheating ... Excluding clinical trial, open to 24, 36, 48, 60, 72 windows amounts to an increase of 6/7; 5.5 / 7; 5/7; 4.5 / 7; 4/7 ... This is additional caution that can provide assurance to the patient, at most: it is pointless.

The medical analysis lab is closed this Monday what should I do?

If this Monday, the lab is closed (vacation, holiday ...): Postpone the blood test for a week. VLs are spaced every 8-9 weeks, but it does not have to be that rigid.

However, if one day you really want to shift, just add a day of taking to the last ON time (eg a Saturday) and go to the lab on Tuesday. So always test the same number of days off. The latest in a period x / 7 becomes (x + 1) / 8 (eg. 5/7 becomes 6/8) which is not a problem, then we resume our schedule on the following Monday.

VL-month 1, VL-month 2, VL-month 4, VL-month 6: why frequent VL?

For a stable patient, viral load is checked every 6 months. This is done to ensure that the strategy, proven on many patients, and apparently effective for the patient, remains very effective, as assumed, but is verified ... It is also checked more frequently during a change in strategy (switch). In particular, to avoid failed drug strategy to be perpetuated : replication in the presence of an inefficient or less efficient drug is an ideal condition to promote a resistant virus: this is also how one selects resistant virus, the laboratory, in test tubes. Such persistance (several months ...) of a situation which combines replication and presence of the molecule, open sthe door wide open to resistance. On the contrary, if it is detected early enough, a rebound in viral load can be resuppressed, and the risk of resistance is minimized.

Patients who fulfil the stricter Premium eligibility (as introduced by ANRS-4D) and perfectly adherent may consider skipping the frequent VL.

The trials validate 5/7 and 4/7 strategies : Why do frequent VL, as in the trials?

In trials with comparator arm (FAUCY, BREATHER), there were fewer viral rebound than in the comparator arm (in 7/7); in trials without comparator arm (FOTO, ICCARRE), there was no failure. Without exception, all the rebounds of viremia were corrected by a simple return to 7/7. To take advantage of this simple and effective management (a simple return to 7/7), detecting a viral rebound (a real one, not just a blip), as soon as possible, seems favorable.

Patients who are strictly eligible to Premium (according to ANRS-4D) and perfectly adherent may consider to skip frequent VL.

Am I at risk of viral rebound?

In trials without comparator arm (FOTO, ICCARRE, ANRS-4D), there was no intrinsic failure: ZERO. In trials with comparator arm (FAUCY, BREATHER), there was less rebound than in the comparator arm, in 7/7. So, there is no excess risk. The trials are very clear on this. With more fraquent VL, the potential consequences are minimal. The number of viral rebound has been so small, in clinical trials, that it is not possible to define a predictor. In ICCARRE 1 and 2 and ANRS-4D, 190 patients were eligible and strictly strictly observant and the conclusion is: failure = 0

If eligible Premium (ANRS-4D): you can skip step 2 and 3, and go direct to 4/7

In ICCARRE 2 and ANRS-4D, patients (approx. 150) are instructed to go directly to 4/7. For those who were strictly eligible and strictly observant one can only observe: 0 failure. So the direct reduction to 4/7, in this context, is validated.

Why a stepstone at 6/7?

The trials go directly to 5/7 (or 4/7 in case of ANRS-162-4D). These patients were highly motivated and medical assistance, at the hospital, before entering the 4/7 was very tight: this does not represent the general case. In France, such a pre-entry diagnostic is easy to implement. Account must be taken of the patient's psychology, for whom the transition to a modest 6/7 may already appear as a secure step. This guide, available on the Internet, minimizes the risk for all and optimizes the psychological comfort for everyone. The stepstone 6/7 gives the time to initiate biological monitoring. It allows the patient to gain confidence that may be necessary in case of unforeseen events (blip, conflict with doctor, etc.). Step 6/7 should be seen as an additional safety, and not as a obstacle. One must enter in the schedule, feel comfortable, and ... move on ... (typically after 6 to 12 months). There is no reason to stop at 6/7.

The first vL at month 1: Why?

This is how it is done in the BREATHER and ICCARRE trials. Then we move to a less demanding pace. Intuitively, until we have have a comforting history, we check more frequently. In the stable phase, we can, after a year of VLs every 2 months, reduce to VL every 3 months (if desired)

My doctor gives me a VL prescription every 6 months

If you are eligible Premium (as of ANRS-4D), and fully compliant, then your doctor may decide that the usual follow-up is sufficient.

A medical laboratory, downtown, can make the viral load without prescription. Just make the request orally. The laboratory makes you sign a document to record that this is an analysis without prescription, therefore no reimboursement. The cost is ca. 60 euros (approximately, in 2015). Consider asking your doctor for additional prescriptions, remember to ask any other doctor you may need to visit. At each visit, specialist or GP, consider asking for prescriptions. Consider doctor change if necessary.

How much will more frequent VL cost?

More frequent VL (every 2 months in the descent phase, and then every 3 months in stable phase), means 6 VL instead of 2 (stable monitoring) and 4 instead of 2. This means 4 more VL (2 or more, in a steady state). At worst, you will pay 60 x 4 = 240 Eu. / Year (20 Eu. / Month) and 60 x 2 = 120 Eu. / Year (10 Eu. / Month)

Consider if you are 'Premium' eligible, as defined in ANRS-4D, this may allow to reconsider these additional VL constraint (although we prefer frequent VL , at the beginning).

For viral load, hospital laboratory or downtown Lab?

RNA quantification (aka viral load) can be done in the laboratory, in town, or at the hospital. The proximity is an advantage. It is a liberal environment, you will have no difficulty to get a blood draw with or without prescription. In Paris, some laboratories have their own PCR machine (ex www.cbcv.fr.) And, therefore, do their analysis on site: it's fast (allow 48 hours; you can get results via the Internet). The vast majority of medical analysis laboratories outsource to laboratory services platforms (eg. Cerba), so it may take more time (allow one week). The result is usually available through the Internet. Fax or in-person pick-up ? this is rare and obsolete...

Unless you have your blood drawn next to the PCR machine, your samples will be carried to the PCR Lab: make sure to get this done before the driver picks-up samples... Inquire, in advance, by telephone, to know the time (and allow yourself additonal time, if a doctor visit is scheduled ), and other possible limitations on dates and times (for example often impossible on Saturday, sometimes impossible on Friday). By phone, it is generally difficult to know the price. In fact, the price is regulated (nomenclature 4122 and schedule B 220 0.27 x 220 = 59.40 Euros in 2015)

see: www.tinyurl.com/HPC-ACTES-2014 (readable) or full NABM

VL without prescription ... The assistant is surprised, what to say?

It is unusual, indeed ... As the regulations allow for it, they will not say no. However, the laboratory must ensure that you are not mistaken in the analysis request, without prescription. To avoid embarrassment (and unnecessary stress), have your answer ready. It's easier to manage if you have another analysis (eg. Blood sugar or Cholesterol) to do with a prescription. Your VL request, without prescription, is more easily justified, since you came anyway... Here are some easily admissible justifications: I return from a trip and I do not feel well. I was on travel and my medication was stolen from me ... I'm leaving on a cruise, so I want to make sure before I go ... I have a new companion, and I want to reassure him ... I'm interrupting treatment, so I monitor carefully... I'm elite controller, without treatment, so I monitor closely... I forgot to take my medication a few days and my doctor will return from vacation only next week ... my doctor allows me to procreate by natural method, so I monitor closely ...

There is no reason it should not to go well ... You have then a document/disclaimer to sign, and that's it ... There are so many labs, so you have plenty of choice ... Keep this in mind.

VL without a prescription, at 60 Euros, this is too expensive for me

You can try to see if you are eligible Premium, as defined in ANRS-4D. The pilot site, in Garches (France), offers assistance to physicians who so wish: it's free. If your diagnostic assessment (to be done before starting 4/7) is good to go, you can consider not to increase the frequency of VLs.

Otherwise ... it's a very reasonable price when compared to other prices (eg. USA $ 400). The most clever ones get prescriptions, enabling 100% refund (sometimes this requires to visit several doctors ...). Do not hesitate to ask. People living as a couple (or allegedly) get it quite easily since undetectability allows for natural procreation, without condom (using SWISS the statement by Hirschel). Frequent VLs are the safety offered to the partner ... Consider also a change of doctors. We find more and more doctors who are supportive of their patients or the couple, and give them prescriptions: just say that you no longer use condoms.

There are no additionnal doctor visits

For the stable patient, the standard routine is to visit a specialist every 6 months (even 12) ... In the 4/7 SAFE program, VL tests are done every 2 months, at the beginning. This is not an additional burden, because in return we use much less medication, it reduces side effects of medication, so, you go less often to the pharmacy, and you visit other doctors less ... In particular, do not visit your doctor at every undetectable VL. There is no need to increase the number of medical visits. The patient visits, gets her prescription for 6 months (or 12 months); every 2 months (and then every 3 months ...), does the VL, receives the laboratory results by internet or fax, mail, checks that the virus remains under the rug, and there is nothing more to do. Once you escape the trap of over medication, you do not want to fall into one of over medicalization. One should do the more frequent VLs, That's all ... Eventually, an annual visit will suffice. Today in France, the order may be valid for one year. Think about it! As soon as we have made a bit of stock, it simplifies life and restores flexibility.

I want to get the vaccine against seasonal influenza. How to manage ?

An infection or vaccination can disrupt the immune system. CD4, thus activated, are a prime target for the virus. So always do things in order: Blood test first, and then vaccination. The same day, the next day, whatever ... but after ... And especially not just before ... The activation period is 2-3 weeks. During the period of vaccination or influenza infection (typically 2-3 weeks), we can, as a precaution, temporarily increase dosage a notch. For example a 4/7, 5/7 switch to during the three weeks of the episode.

consecutive days: Why?

Days WITHOUT drugs are consecutive days (eg Saturday and Sunday.): This how it has been done in clinical trials: it is easier to manage. Resume on Monday, it's like work, school, etc. The body rests continuously. Consecutive rest days allow the body to recover: the cycle in short is not the non-adherence. The body reloads continuously in molecules. Using the weekend break (or long weekend) we facilitate proper monitoring of the cycle.

(e.g. Monday-Tuesday-Thursday-Friday) Alternative rhythms were sometimes considered: only the small trial A-TRI-WEEK followed an alternative rhythm.

The plateau lasts six months: Can I do less?

The SAFE program is 4/7 careful: it avoids the overmedication (deleterious) while maintaining undetectable virus. Why hurry? Better to take your time and be successful than taking the risk of having to go back. For 4 most tried combinations, for which the cumulative number of patients is approx. 300 patients (with no additionnal risk), we can shorten a bit the 6/7 plateau. The 4 most tested combinations are: Atripla ® (or Sustiva ® + Truvada ®) (= EFV / TDF / FTC), Viramune ® with Truvada ® (= NVP / TDF / FTC), Sustiva ® + Kivexa ®) (= EFV / ABC / 3TC), Kivexa ® Viramune ® + (NVP = / ABC / 3TC) ... Knowing that you have an entire life ahead ... At nay rate, do not overlook the frequent VL!

For Premium eligible patients (= according to ANRS-4D) the progressive ramp up 6/7, 5/7, 4/7 may be unnecessary.

The last six months tray: Can I do more?

Yes, why not ... With the combinations already tested (see above), stay 48 months 6/7, it's a shame ... But we can make longer shelves: 12 months and up.

Place 5/7 to 4/7 there a risk?

The Faucy trials, Foto, Breather has been made 5/7. In ICCARRE-1 trial, Dr. J. Leibowitch increased from 5/7 to 4/7 in all 48 patients without failure. In ICCARRE-2 test, it passed directly from 7/7 to 4/7 in fifty patients without failure. The ANRS-4D (results published in July 2016) is testing the 4/7 live on 100 patients. No excess risk was identified in 98 of Garches (ICCARRE 1 and 2) or in ANRS-4D. This is a significant number of patients, so the transition from 5/7 to 4/7 is possible without identified risk and over-precautionary and monitoring of this guide are to be followed carefully.

Stabilizing at 4/7: why not go to 3/7?

Exploratory trials show that by starting from 3/7 (included) there is a risk of failure. It is particularly marked with triple therapy containing raltegravir (Isentress ®) or protease inhibitor (Kaletra ®, Prezista ®, ...): Do not try with these combinations. The risk is less with the use of NNRTI (eg Atripla ®, Viramune ® + ... + Sustiva ® ....); to reduce this risk to zero, J. Leibowitch adds a third NRTI. Adding the 3rd 3/7 INTI makes both safer and less attractive: instead of taking 4 days 3 molecules, it takes 3 days 4 molecules. Toxicity or 12 units in 2 cases, to gain a psychological and marginal practice. Except for patients considering the 2/7 (or 1/7), which is the subject of a separate experimental guide, the 3/7 (as cruising speed) does not have enough interest (in terms the addition of a molecule), so it is not considered as part of this practical guide.

The existence of Hypo-Dolu proposal (maintenance dolutegravir with mono-therapy (Tivicay ®) in 1/7) suggests that the 3/7 is possible with tri-based therapies dolutegravir. Sure ... But in that case, why not focus instead on Hypo-Dolu?

The guide stops at 4/7 ...

View 1 doctor once a year ...

Apart from the initial period, where visits are more common for a patient 'stable' rhythm is once every 6 months ... Beware of doctors who figure on the backs of patients 6 months ... that's ... 12 months is quite possible you may require. As the stock will start to accumulate if a simple renewal of consultation falls ill, well ... nothing will oppose and cancel from the sin. This gives some flexibility, and leaves the patient, as the doctor the free enjoyment of his leave. Do not miss to his CV.

2 go to the pharmacy once a year ...

Some patients are unnecessary tens of kilometers to get their drugs to the hospital pharmacy ... What wasted time and unnecessary stress. Except in special cases, the issue can occur in any pharmacy: close to work or home, etc. There are so many, and some of their tongue ... You should know benefit: the Safe-Generiques.pdf guide shows how to do it: Make mention of the order: the FAQs ISSUE 2 MONTHS for professional reasons. You just have to find an obliging pharmacy (all are not, but they are numerous, smaller may be more accommodating ...). Think prevent your stay.

Go to Lab 4 to 6 times per year

Since it is known to reduce the number of visits to the pharmacy, a few extra visits to medical analysis laboratory are not an additional burden. Prefer labs that provide the results (including HIV) by Internet. Inquire by phone. In Paris, the CBCV give you satisfaction.

Total ICCARRE is less interaction with healthcare professionals ...

Pharmacy is a grocery store, do not count on the pharmacist for advice on sharp ARVs ... Le Labo, a place of sampling, at most (they know mostly longer use PCR). The doctor may be helpful, if it is good ... For the patient 'stable', reducing this kind of interaction, psychologically heavy, but of little value, can help the well-being ... The stable patient non- ICCARRE two specialized consultations, blood tests 2 and 12 passages in the pharmacy. The well-organized patient ICCARRIEN 4-6 passages at the pharmacy, 4-6 in Labo, 1-2 to the doctor. The ICCARRIEN and strictly Premium eligible patient (= the meaning of ANRS-4D), well organized, a 4-6 passages at the pharmacy, 1-2 in Labo, 1-2 to the doctor. 16 without ICCARRE, 9-12 with ... And ... 6-10 with Premium. This is already something gained ...

Medical monitoring: desirable but can do without it if necessary

Indicate that medical monitoring is desirable is a concession to political correctness. It is desirable ... Provided, of course, consult a physician experienced in the short cycle in relief ... Consult a physician who is not trained or which is, moreover, a consultant for the pharmaceutical industry, ie, is like asking a tobacconist how to wean tobacco. Since doctors who know how to do are quite small, we can make 10 doctors before finding one that can help you. Help you in what way? Check with you that you are eligible? If your history is complex, and that the doctor knows the details of your journey, and possibly of past resistance would be helpful.

When?

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