French guidelines updated
Translation and commentary by Simon Collins and Emmanuel Trenado for HIV I-Base
In 1999 the French Ministry of Health published guidelines for the treatment and management of HIV infection that were amongst the most practical and forward looking of their kind (see DrFax no75). They have now been revised and the new report was published in December 2000. We include below a translation of the introduction for this and summary and recommendation of the main points.
Careful management guidelines are provided for treating patients with metabolic complication. It is disturbing that metabolic disturbances are recognised as occurring in over 50% of patients but encouraging that their gravity and frequent occurrence are acknowledged. Also, that the seriousness of facial atrophy is recognised by the provision for some reversal/corrective treatments to be available within the National Healthcare system. The essential importance of reporting all serious and unexplained instances of toxicity (notably myocardial infarction and bone disorders) to a national safety register is also stressed.
As with the 1999 guidelines, IL-2 remains a recommended treatment for patients of achieve undetectable levels of viral load but whose CD4 counts remain <200 cell/mm3.
The full summaries, together with the complete guidelines (in French) are available at the following website:
Compared to previous years, the care of HIV patients has more to do with long term care and problems of tolerance, toxicity and the acceptability of treatment are now major issues in the care of HIV-positive patients.
In the absence of new classes of antiretrovirals, eradication is no longer either a short or medium-term objective, and the goal of treatment has shifted to immunological and virological equilibrium over the long term assisted by immunotherapy.
The panel of experts involved in these recommendations decided to provide an update to last years guidelines rather than completely rewrite them. The report is more focused this year on the therapeutic care and issues. The questions surrounding the care of certain categories of HIV-infected patients such as IVDUs, prisoners, immigrants, women and lower income groups, will be dealt with in a future report. This is also the case for prevention, testing and primary care.
Eleven chapters have been updated and new recommendations have been included in all these chapters. Summaries have been provided for the most important points and these are included below. Among them we particularly stress the reformulation of our general therapeutic strategy including:
- the need for long term care of patients (because there eradication is less hopeful)
- the frequency of side effects
- but also the efficacy of HAART therapy even when starting with a depleted immune level.
- On the therapeutic level the following points deserve to be stressed:
- treatment is now not recommended while CD4 levels remain >350cells/mm3 if immunological and virological situation of the patient is stable
- three different HAART combinations are available when considering an initial treatment regimen (PI + 2 RTIs, NNRTI + 2RTIs, triple RTI)
- the use of low dose ritonavir with a PI that allows simplification of standard PI-containing regimen
- therapeutic interruption of treatment in patients who are have responded immunologically and virologically to treatment (i.e. are currently with an undetectable viral load) should be reserved for protocols within a clinical research. Nevertheless, it is essential to inform and monitor closely patients who take the decision to interrupt their treatment.
To succeed in the care of HIV-infected individuals requires recognising the two key components of an individualised and multidisciplinary approach.
Compared to last year there are two positive points that have lead to improved care:
- good accessibility to genotypic resistance tests
- better use of TDM in the care of HIV-infected patients (although the use of TDM for patients using PI-containing regimens still remains under utilised).
On the other hand the care and diagnosis of people co-infected with HCV and HIV patients still needs to be improved.
Several areas that remain important have not been addressed in these recommendations including:
- that over half of all treated patients continue to maintain a detectable a viral load. The cause of a failing regimen are essentially linked to problems with adherence and resistance. The situation of heavily treated patients who are failing all regimens (approx 6% patients – of the 80,000 people in France on treatment) always remains a preoccupation. The programme for combining new agents (such as the ANRS Puzzle Studies) in the setting of clinical trials continues to develop too slowly.
- the number of women infected with HIV is growing and the care of these women must be improved especially in the areas of gynaecological care, and the desire to have children and management of metabolic changes and lipodystrophy.
In the 1999 report the panel stressed their worries about the level of patients seen for the first time at a clinic without a previous history of treatment, especially among immigrants and those from a less economically advantaged background. We now know this is not a worry but a reality. After the decline and levelling out of AIDS cases from 1996-98, the number of new AIDS cases remains sadly stable for the last two years. 50% of the patients seen who receive an AIDS diagnosis did not previously know of their HIV-positive status and were not being provided with medical care. 25% knew their status but were not being monitored. Many of these patients were infected through heterosexual transmission.
The perception of AIDS has considerably modified since the introduction of HAART therapy, in particularly among young gay men. The different players in the fight against AIDS – community organisations, doctors and the government need to develop new ways to counter this apathy, to promote prevention measures, to improve access to testing and to ease access to care in patients infected with HIV.
The 1999 report announced a reorganisation of the use of epidemiological data to be able to comment on a more recent period. This has been delayed. No new element allows us to believe that there has been a regression in the spread of HIV in the general population. Nevertheless, the interpretation of the new epidemiological markers, confirm the impact of the new HAART therapies on the incidence of opportunistic infections and mortality.
Therefore this results in an increase in the number of people living with HIV in France and the number of newly infected HIV people, even if slightly diminished, is still at an important level. Finally, 20% of the people newly diagnosed with HIV are diagnosed with AIDS. This shows there is an insufficiency in the policies for diagnosing and caring for this group of people.
- To develop the epidemiological surveillance of the HIV infection. France is behind in this respect.
- The surveillance of sexually transmitted infections remains a good indicator of any relaxation in prevention measures
- To improve epidemiological research to estimate the prevalence of HIV infection and to provide greater detail about the characteristics of newly infected patients at diagnosis
Since 1999 the availability of genotypic resistance tests has greatly improved across France. Their use is essentially indicated in people failing their first regimens. This enables us to optimise the changes of treatment in order to spare as many antiretrovirals as possible for the future.
- To prescribe resistance tests only once a decision to change treatment has been taken.
- To interpret results in a collaboration between virologists and specialist clinicians
- To continue with clinical trials to better establish an indication for use of these tests
Because of the frequency of side effects, the difficulty of adherence and the possibility of immune restoration even when treatment is initiated at a late stage, lead us to reformulate when to start antiretroviral treatment.
- To defer treatment in all patients with CD4>350 when the immunological and virological situation is stable.
First line treatment
Three different ARV combination are recognised for use in first-line treatment (PI + 2 RTIs, NNRTI + 2RTIs, triple RTI)
With patients having a viral load level >100,000 copies/ml and/or CD4 count <200 cells/mm3 the use of a PI + 2 RTIs has been better evaluated. With these patients it is appropriate to consider a 4-drug regimen,
With patients maintaining immunological and virological control with a first-line therapy consisting of a PI + 2RTI, it is possible to change the PI to an NNRTI, and probably to abacavir without the risk of virological rebound. This is only the case with first line therapy and previous nucleoside treatment, such as ZDV, increases the risk of subsequent rebound.
With patients treated successfully, a structured treatment interruption (STI) is always accompanied by a rebound in viral load levels. This does not appear to have a negative effect in the short term.
- It remains inappropriate to use an STI strategy in clinical practice outside of a clinical research protocol
- To inform and closely monitor patients who have decided to interrupt treatment. Doctors should bear in mind that in the majority of cases their virus will remain sensitive to the initial treatment.
- Careful monitoring should be provided whenever reintroducing abacavir, even if an abacavir-containing regimen was previously well tolerated in the first regimen.
The rationale for use of immunotherapy intervention developed in the 1999 guidelines has been confirmed. Specific observations relating to IL-2 are listed below.
- Use of IL-2 in patients with a CD4 count >300 cells/mm3 has been confirmed in terms of increases in CD4 without associated risk of viral load increases, but the clinical benefit of this is still being investigated in a large international study (ESPRIT).
- Following the results from the ILSTIM study, the use of IL-2 in patients with low CD4 cells (<200 cells/mm3) is now possible in routine clinical practice (through the French ATU expanded access programme). By the end of 2000, over 250 patients had benefited from this treatment.
- The international SILCAAT study is currently investigating the clinical benefit for patients starting with CD4 counts <300 cells/mm3 and a viral load count <5000 copies/ml.
Systematic treatment of all people in primary infection is not recommended.
- To continue to initiate antiretroviral treatment with patients presenting with serious symptomatic and recent primary infection (< 1 month), preferably within a clinical protocol or cohort study
- To discuss the possibility of treatment in cases of primary infection presenting with only mild symptoms and/or a late diagnosis
- To delay treatment in patients that have no symptoms and/or serologic markers have all proved positive and seroconversion has been completed.
- When a treatment is started, it is difficult to be clear about the necessary duration, without results from clinical trials?
Comment: This section does not take account of the recent findings from Bruce Walkers group in Massachusetts showing that people starting treatment in primary infection can stop treatment and control HIV with their own immune system (see HTB October 2000). The reaction against treatment in primary infection in France is also partly due the previous pressure on patients to begin treatments that were difficult to tolerate or adhere to (i.e. full-dose ritonavir-based regimens).
Over 50% patients treated with antiretrovirals present with various degrees of metabolic disorders. These have been observed with all the available classes of drugs. The mechanism for these disorders are still very difficult to elucidate.
- On starting treatment, patients should be offered an evaluation of cardiovascular risk. As a preventative measure a risk reduction programme should be proposed that includes: stopping smoking, weight control, diet and nutrition support, treatment for hypertension where appropriate and an exercise programme.
- To offer full evaluation of metabolic lipid and glucose levels every 6 months.
- That it is essential to notify all cases of bone disorders and myocardial infarction to the French pharmacovigilence agency. (The report notes that about 70 cases of osteonecrosis were reported in France during 2000, although other associated risk factors such as alcoholism or corticosteroid use could be identified in many of these cases).
NOTE: The chapter on metabolic changes also makes specific reference to facial lipoatrophy, and comments on several interventions not yet routinely available in the UK including:
Several techniques to improve these symptoms are possible but only two of these have been evaluated in France for facial lipoatrophy. They are accessible and available only to a limited number of patients. The cost is high but they can be reimbursed by the healthcare system in some cases. It is recognised that they are offered in limited settings.
These techniques are:
- Fat transplant from one site of the patient to the affected area – the `Colleman’ technique. Early data has shown encouraging results persisting for >6 months.
- Fill products. Injection of polyactic acid (New Fill) might provide prolonged results and is currently being evaluated. The use hyaluronic acid has only provided transient benefit (2-6 months). Bovine-derived collegen implant is allergenic.
The use of permanent filling techniques, for example, gortex or plexiglas (collagen-derived) or hyaluronic acid are specifically NOT recommended in the guidelines.
- To offer patients starting treatment an evaluation of cardiovascular risk, and as a preventative measure to propose a risk reduction programme: stop smoking, weight control, diet and nutrition support, treatment for hypertension where appropriate and an exercise programme.
- To offer full evaluation of metabolic lipid and glucose levels every 6 months.
- To notify all cases of bone disorders and myocardial infarction to the French pharmacovigilence agency.
A full protocol for managing hyperlipideamic patients with increased risk of atherosclerosis is also included in the guidelines.
Therapeutic drug monitoring (TDM)
The chapter on TDM comments that in September 2000, over 2500 drug levels samples were processed in laboratories across France. Although highlighting the need for increasing use of TDM in the introduction, this indicates that TDM is a technology that is very much being used in France.
Issues of validation and interpretation are addressed and a therapeutic range for each drug is provided. The main issue in this section deals with the use of low dose RTV with another PI which permits a simplification of ARV regimens by boosting the concentration of the associated protease inhibitor.
The guidelines also report a wider flexibility for dose adjustment than is routinely practiced. For example, when dosed with 100mg of ritonavir BID, the associated indinavir dose recommended is between 400 and 800mg BID providing that this is only used with the support of TDM.
- To monitor PI drug levels in the first weeks following the start of treatment and to check this level regularly to better control doses and prevent side effects due to high doses.
Assisted fertilisation techniques
There has been an increase in sero-discordant couples where the man is HIV-positive for access to sperm washing techniques. For legal reasons the healthcare system has not been able to offer these techniques.
- That the State organise access to this techniques as soon as possible.
Prevalence of HCV in HIV-infected in high. HCV is aggravated by HIV coinfection. Coinfection increases the mortality risk.
Diagnosis and care for HCV in people infected with HIV are currently insufficient. The indications for treatment though haven’t changed since 1999. It is recognised that the use of interferon + ribavirin is less effective than in HCV-only infected patients.
- To diagnose for HCV in every HIV infected patient
- To improve the care for patients with alcohol associated problems
- To offer liver biopsy, the main indicator for HCV treatment, to all HCV-infected patients