How to treat a recent contamination Over the past few months, two new notions have been added to the HIV-related medical jargon : "emergency treatment" and "treatment of primary infection". Both deal with persons recently exposed to a contamination. However, their objectives, duration, and medical prescription procedures differ. It is therefore important to detail them. Emergency treatment is intended for HIV-negative persons who have been at risk of being contaminated by HIV (needle injury or sexual contact). It must be implemented within hours (or, at the latest, within 2 to 3 days) following exposure. It is believed that, in a majority of cases, contamination will be prevented (see frame below, and Remaides issue n° 24, p. 30). Treatment of primary infection occurs later. It is intended for persons who have been infected by HIV one or several weeks before. This has never been shown to eradicate HIV from the body. However, it is hoped that this will slow down the course of the infection (see p. 16, 17). To understand each of these treatments, it may be helpful to review what occurs in the body of a person who has just been exposed to HIV, through needle injury or sexual contact. Just after contamination In the hours following contamination, the virus is present in the blood and spreads through the body. Two to three days later, it is present in various organs, and also in sperm and vaginal fluids. The virus continues to replicate very actively for a few weeks, and T4 lymphocytes cell count decreases, sometimes in a significant way. However, HIV's presence stimulates the immune system into reacting. It is at that time that anti-HIV antibodies start appearing in the blood (even though, at first, they are not present in sufficient amounts to be detected by screening tests, see figure). Symptoms of primary oinfection In over half the contaminated persons, immune system reaction leads to the appearance of one or several symptoms (called "symptoms of primary infection"). They usually occur one to four weeks following exposure to the virus and often last from two to four weeks. They sometimes resemble flu symptoms. Fever, swollen glands, skin spots or rashes, muscle or joint pain, headaches, nausea, diarrhea, etc. Thus, if this type of symptoms appear one to four weeks after being exposed to a risk of contamination, it may be advisable to consult a physician to consider an early screening test (see frame). If positive, the opportunity to treat will need to be discussed. How does infection evolve The immune system's activation occurs progressively. The number of T4 lymphocytes goes back up in a few weeks. The amount of HIV in blood (viral load) goes down and, approximately three to six months after contamination, stabilizes itself. It usually remains at the same level over several months. Once it is stabilized, if viral load remains high, the risk of evolution of the HIV infection in the following months or years is thought to be high. Conversely, if the viral load is low, this risk is low (see new US guidelines p 6,7).
The emergency treatment "Emergency treatment" has been instituted for several months to deal with caregivers who experience pricking injuries or cuts while caring for an HIV- seropositive patient. In July, Bernard Kouchner, Health Secretary, sent a letter to hospitals urging them to consider extending this treatment to other situations. Some institutions have already implemented these recommendations (see Remaides issue n° 24, p 30), other are awaiting firm instructions. A working group on the treatment of recent contamination has been meeting since May at the Health Ministry. Several AIDS groups, in particular AIDES, take part in these talks. This group should make recommendations in October. What to do, concretely, after a risk of contamination? (broken condom with an HIV-positive partner, for instance) ? Start by washing very gently the outside of the anus, penis or vagina with lukewarm water. Call the closest hospital (only hospital doctors can prescribe these treatments). During business hours, ask for the department dealing with patients infected with the AIDS virus. Explain what happened to a physician. During evenings, at night and on Sundays, ask for the physician in charge of the emergency treatment of caregivers (there is normally one such physician per hospital). These physicians are often linked with the Emergency Room. Go to the ward and ask for the physician to whom you spoke on the telephone. He/she will assess the situation to evaluate whether a treatment is justified. If you have been unable to call, go directly to the Emergency Room. You may have to insist to be referred to a physician who is knowledgeable about this topic. If you are reluctant to go directly to a hospital, you can go to a "CDAG" (Centre de Dépistage Anonyme et Gratuit). There, you will see a physician who will assess the risk and, if necessary, will refer you to a hospital physician. You may also call Sida Info Service or an AIDS group to know which hospitals have implemented emergency treatments. It is important to remember to do all this quickly, in the first hours following the risk of contamination (two to three days at the latest, before the virus spreads into the body). Treatment must be taken regularly for four weeks, closely following instructions regarding how drugs need to be taken.
Early screening Until recently, persons who had experienced a risk of contamination were advised to wait for three months before a screening test since "classical" tests actually look for anti-HIV antibodies. These can only be detected once they have reached a sufficient level, usually one to three months after contamination. In fact, it is know today that HIV multiplies itself extensively in the body well before this occurs. It is present in large amounts in the blood a few days following contamination. This is why tests which directly detect the virus can be performed at that time (approximately 10 days after risk of contamination). They may consist in viral load determination or a less costly test reported to be as effective in this situation : p24 antigen count. This test detects HIV p24 protein in the blood. Viral load test could until now only be performed in a hospital. Private laboratories should be able to perform it starting in October (see p 8,9). In actual practice, today, a person recently exposed to a risk of contamination can have a double test performed : p24 antigen count and a classical ELISA test (anti-HIV antibodies). These tests can be performed in most "Centres de Dépistage Anonymes et Gratuits" (CDAG). Sida Info Service or the nearest CDAG can provide you with additional information. This early screening makes it possible to detect some, but not all, early contaminations. Therefore, to be certain not to have been contaminated by the HIV virus, a classical test (ELISA test, anti-HIV antibodies) must be performed three months after the risk of contamination occurred.
After the contamination 
This figure shows what usually occurs in the blood in the weeks following contamination : T4 levels go down, viral load and p24 antigen count go up, anti-HIV antibodies appear progressively. The "viral boom" phase is also that in which the immune system activates itself and primary infection symptoms may appear. To know more, to assess a risk of contamination, please call Sida Info Service : 0800 840 800 (in France). Is a treatment needed at the time of primary infection?
In the weeks following contamination by HIV, the virus multiplies itself very actively, while the immune system starts reacting : this is the primary infection phase. Is it beneficial to start a treatment at that time ? An ongoing trial aims at answering this question. Primary infection treatment must not be confused with the emergency treatment. The primary infection treatment, which is this article's topic, can be implemented in the weeks following contamination. It cannot prevent contamination. However, it is hoped that it will slow down the course of HIV infection. Many physicians believe this, but, at present, there is no proof to substantiate this belief. This is why clinical trials are necessary.
One such trial has been set up by the "ANRS" (Agence Nationale de Recherches sur le Sida) : see paragraph "the current Frech trial". However, not all hospitals participate in this trial, and many primary infection treatments are prescribed outside of this framework. For these treatments to be prescribed or not depends on the doctor's conviction and that of the patient. Some clinicians prescribe double combination therapies, other prescribe triple combination therapies. Other do not prescribe anything at all. When , for whatever reason, no treatment is prescribed for primary infection, the patient should be followed-up under the usual medical procedures. A treatment may start being prescribed only several months or years later, depending on the evolution of the viral load and T4 cells (regarding this topic, please see "The new US recommendations"). Who needs to be treated for primary infection ? During the weeks following contamination, over half the persons exhibit symptoms (fever, swollen glands, sore throat, skin spots or rashes, muscle or joint pain, headaches, nausea, diarrhea, etc.). These events can mimic symptoms associated with other illnesses, such as the flu. Their intensity varies considerably from one person to the next. They usually disappear spontaneously in a few weeks. Studies show that persons who exhibited major signs of primary infection have, on average, a higher risk of evolution of HIV infection, compared with persons who did not exhibit such signs (or for whom they went unnoticed because they were mild). Trials of treatment of primary infection therefore primarily target people who developed clear symptoms during that period of time. A trial with AZT alone A study using AZT (Rétrovir®) as a single agent has already been performed. Patients took this drug for six months starting at the time of primary infection. Their symptoms subsided more quickly and their T4 levels went back up faster than persons who did not take AZT. Of note, T4 levels usually go down during primary infection and then go back up again (see p. 14, 15). A few months after discontinuing AZT, these persons did not show any difference (in terms of T4 cell count or viral load), compared with those who did not take AZT. Would a combination therapy (with two or, better, three drugs) give better results ? Triple combination therapy : first data A few persons have received a triple combination therapy including a protease inhibitor during trials in France and in the US. In a large majority of these patients, viral load became undetectable (that is, too low to be detected by current tests), and remained so over several months (data regarding longer follow-up periods are not available). Interestingly, lymph nodes of some of these patients were looked at and, in several instances, HIV could not be found. However, the virus probably did not disappear altogether : some patients discontinued treatment and their viral load went up in the following weeks. The current French trial The current study (ANRS 053B) involves a triple combination therapy (Norvir®, Rétrovir®, Épivir®), for 18 months. This trial is intended for persons who experienced at least two symptoms of primary infection following a possible contamination. Contamination must, naturally, be confirmed by an early screening test (see P 14-15). Adverse events are those usually associated with triple therapy including Norvir® : nausea is often seen during the first weeks of treatment, but usually subside thereafter. How long should the treatment last for ? It is not known how long a treatment for primary infection should last for : six months ? eighteen months ? indefinitely ? This question is related with the goal which is ultimately pursued : a few scientists believe that a sufficiently long treatment (two to three years) could totally block the replication of HIV and lead to its disappearance. This is, at the moment, an entirely theoretical hypothesis. Most physicians who favor treating primary infection think that this will slow down the HIV infection's evolution. It has been known for one year that this evolution is linked to the viral load. This does not apply to the primary infection stage, during which viral load is always very high, but to the following months during which viral load stabilizes itself, after decreasing for a while. It is clear that treatment brings down the viral load. Triple therapy, given at the time of primary infection, seems even more efficacious that when it is given in the usual circumstances (in people who have been HIV-positive for several years). What will happen when treatment is discontinued, as planned in the ANRS study ? Will viral load remain low or will it go up ? If it goes up, this probably means that the benefit of treatment will be lost. Should treatment be maintained for longer periods of time ? Or even, as some doctors believe, indefinitely ? A few caveats Several arguments can be used to justify being cautious in the face of more and more doctors' enthusiasm for treating primary infection. It must be remembered that reatment is initiated at the time when viral load in blood is at its peak. Thus, the more viruses exist the higher the risk of not being able to fully master their replication. Could we not see, under these circumstances, appear viruses which are resistant to the drugs used to fight them ? In addition, the immune system is activated by primary infection. This is due to the presence of the virus. Couldn't a treatment which dramatically reduces the amount of HIV risk to block this activation ? As a conclusion Arguments pro and con treatment of primary infection are many and often complex.. One can hope that ongoing trials will bring answers which will end the debate. But this is not all : such a daily treatment requires a psychological support which no existing structure can provide. For affected persons, this means taking for an indefinite period of time a treatment which efficacy has not been proven, at a time when they just learnt about their HIV-positive status and in spite of feeling in good health. These are many issues to manage. Psychological support could facilitate a regular dosing of drugs, critical to their efficacy. It would be, at the very least, necessary to help these persons go through a period of time often characterized by anxiety.
The benefits of treating primary infection are being investigated.
ANTI HIV MEDICINES : THE NEW U.S. RECOMMENDATIONS At the end of June, the National Institute of Health and a group of international experts issued new recommendations concerning the use of anti HIV medicines. The objective of the treatment is to maintain a viral load below the detectable level. The French recommendations should follow in September. They will be fully efficient only if HIV- infected patients are informed enough to understand what their treatment means and receive better advice about what kind of treatment they should choose and why they should choose it. The level of the viral load predicts the clinical progression of the HIV infection: this is one of the conclusions of the 1996 Vancouver International Conference. The objective of the treatment is to reduce the level of the viral load. When viral load is lower than 10.000 copies/ml (4 log), the risk of progression of the disease is reduced. But, since last year, we know definitely more on that matter. Nowadays it is known than when the process of replication of the virus is continuing, even very slowly, there is a higher occurrence of resistance. This is particularly true with medicines like Epivir®, Viramune® or the four protease inhibitors (Norvir®, Crixivan®, Invirase® and Viracept®). Consequently, the treatment's objectives have been clarified: in order to be as efficient as possible during the longest possible period of time, it is definitely better to obtain an undetectable viral load level (lower than the limit of detection of the tests used). These data have been used as a basis for the new American recommendations. They can be summarized as follows :
ABOUT A STRONGER TREATMENT When one goes into treatment (or when one changes treatment), the strongest combinations should be chosen to obtain and maintain an undetectable viral load for as long as possible. A group of international specialists suggest to begin treatment by a triple combination therapy including a protease inhibitor rather than by a double combination therapy. It could be also possible to begin a triple combination therapy without a protease inhibitor for those who are intolerant to protease inhibitors (discomfort or severe side effects). ABOUT AN EARLIER TREATMENT Last year, it was recommended to begin treatment when the viral load was higher than 30.000 copies/ml (4,5 log). This year, it should be possible to begin treatment with a viral load of 10.000 copies/ml (4 log). If the viral load is higher (after confirmation by a second test), it is possible to begin immediately an anti-HIV treatment whatever the T4-cell count is. The treatment must begin before the immune system is damaged: first, because it is the best way to preserve it, second, because an healthy immune system completes the action of the treatment and reduces the side effects. Meanwhile the beginning of a treatment must not be considered like an absolute priority: it is definitely more important to get informed about which medicines are on the market and what are the best combinations to take according to one's own lifestyle. It is also necessary to be psychologically prepared to assume the long term commitment required by an antiviral treatment (an all-or-none commitment for several years or perhaps the rest of a lifetime). An interview with the doctor, precisely on that subject, is highly recommended. Several interviews could be necessary. A doctor must not give a prescription concerning the beginning of a treatment or a change of anti-HIV medicines without taking the time to talk about it. ABOUT CHANGING TREATMENT EARLIER American recommendations suggest to change treatment as soon as the viral load becomes detectable again, in order to reduce the occurrence of resistance. Meanwhile, before making the decision to change treatment, the results of a second viral load test must confirm the first one's. It can be done one or two weeks later: it is not recommended to wait for 3 months. Why change treatment when the viral load becomes detectable again? Because that means that the HIV virus is again in a process of replication in spite of taking medicines. It is highly probable that resistant viruses had already appeared, even it's a small amount of them. The development of resistance is a gradual process: when the viruses replicate, the level of resistance to the medicines is going to increase. Furthermore, they can become resistant to others medicines of the same family. This is call cross-resistance. Cross-resistance exists between medicines of the same family as AZT, but also between protease inhibitors: a virus which is highly resistant to Crixivan® is generally resistant to Norvir®, and could be resistant as well to Viracept®. It doesn't mean the patient must avoid to try Viracept® when Crixivan® doesn't work anymore: it is very difficult to predict how each metabolism is going to react. But it is generally admitted that it is better to change a treatment as soonest as the viral load becomes detectable again, rather than wait for the appearance of strong resistances (and probably cross-resistances). Actually only the lowest possible viral load (lower than the limit of detection: less than 200 or less than 500 copies/ml) indicates that the virus activity is under control. This observation will be better supported when more powerful viral load tests will be on the market (level of detection at 20 copies/ml). As a matter of fact, studies have already shown that the occurrence of resistance is practically non existent when the viral load is below 20 copies/ml, on the other hand it still exists when the viral load is between 20 and 500 copies/ml. ABOUT A CHANGE FOR A STRONGER TREATMENT When a treatment has to be changed because of a new increase in viral load, it is better to totally change medicines. If this is not possible (because of problems of tolerance or because a lot of HIV medicines have been already taken in the past), the solution is: to change most of them. This recommendation is not new, but strangely enough it is not enforced by all doctors. David-Romain BERTHOLON
HOW TO LIVE WITH... Nowadays the best ways to use anti HIV medicines are largely known. But in order to bring real benefits in terms of quality of life and survival, those strides of the science might go with a range of measures to support HIV positive persons. The experience of people taking protease inhibitors from the very beginning shows that taking these medicines very regularly during a long period of time is not at all obvious. To continue such a treatment, the patients must be convinced of its efficiency and be strongly motivated. It implies that HIV positive persons be well informed and supported before the beginning of the treatment and while it lasts, as often as they need it. Support can be found from a number of sources: : nurses and doctors (at least those who know how to speak to patients), volunteers from associations,(especially AIDES), Sida Info Service and its new "Life Line" (see on page 5), etc... But those facilities are far from meeting the needs and quite a lot of persons under treatment do not receive any support. It is clear that the best place to bring such a support to people is the hospital or any place where patients are attended. A new job could be created : adviser. Such an adviser could take the time necessary to listen to the patients, helping them to take decisions, see how introduce combination therapy into their lives, organize their time table, etc. That could be, in a way, the associative know-how at the patients disposal. D.-R. B. et T. P.
Implementing new guidelines is not always easy ! Antivirals in non-hospital pharmacies: last fine-tuning before D-day.
More than one year after it was announced, the possibility of obtaining anti-HIV drugs in both hospital and non-hospital pharmacies should become a reality at end of September or early October. Negotiations between the Health ministry and pharmaceutical firms will then be completed. Meanwhile, regulations protecting the rights of HIV-positive persons will have been finalized. Up to now, a physician's prescription for anti-HIV drugs could only be handled by hospital pharmacies. This system had been set up at the beginning of the epidemic because of the special nature of these drugs: these are new, costly drugs about which little is often known. This system also served to protect confidentiality at a time when AIDS was an especially stigmatizing disease. One of AIDES' demands The Government has been willing to have non-hospital pharmacies deal with these drugs for several years. From the onset, one of AIDES' demands has been that a double dispensation system be set up: yes to drugs being available in non-hospital pharmacies, as long as patients can keep the option of getting drugs from the hospital if this is more convenient for them, or to ensure confidentiality. Indeed, in many places, HIV-positive persons encounter difficulties with confidentiality, anonymity and more generally to defend their rights, especially in the DOM-TOM (French overseas territories) or in small towns. Anonymity is often better ensured in a hospital than in a neighborhood pharmacy or a small town one. In 1995, after years of stalemate and refusal to set up this double dispensation system, the Health Ministry and the "Direction générale de la Santé" finally accepted -for the first time in France- this innovative system of drug dispensation. Which drugs are concerned ? Antiretroviral drugs (anti-HIV drugs) with a marketing license ("Autorisation de Mise sur le Marché" (AMM)) will be available from either type of pharmacy: Rétrovir®, Zérit®, Videx®, Hivid®, Epivir® (reverse transcriptase inhibitors) and Norvir®, Crixivan® et Invirase® (protease inhibitors). In theory, all these drugs should become available under the double dispensation system at the same time. This will enable the delivery of the most commonly prescribed double and triple combination therapies. Only Hivid® will have to wait for a few months, because of issues related with its registration file. However, drugs such as Viracept® et Viramune® which are only available through a Compassionate-use type of program called "Autorisation Temporaire d'Utilisation (ATU)" will only be available from hospital pharmacies. Information documents To help with the information of HIV-positive persons and health care workers, the Health Ministry and the "Agence du médicament" have issued two information documents. The "patients" brochure includes information on antiviral drugs, the double dispensation system, drugs side-effects, instructions for taking drugs, etc. Fell free to ask your pharmacist for a copy if he/she forgets. This document is intended to be used by you but it can also help persons around you, for instance those who help you take your drugs. You are free to choose your pharmacy No hospital pharmacy will be able to turn down your request for drugs under the pretext that they are also available in town, and vice versa. Be careful: some hospital pharmacies will be tempted to pass on the workload involved in the dispensation of these drugs by directing you towards non-hospital pharmacies. Under all circumstances, your preference must be respected. You may go to any hospital pharmacy, even though it is not that of the hospital you attend or the city where you are followed-up. The same applies to non-hospital pharmacies. For instance, when you are on holidays, you can get your prescribed drugs from any pharmacy on the French territory. Who will prescribe ? The first prescription, or treatment change will need to be made at the hospital. If you are followed-up by a general practitioner, he/she will be able to renew this first prescription or modify the dose of a drug prescribed in the hospital, for one year. After one year, you will need to see a hospital doctor for a check-up and a new prescription. However, drugs can be dispensed by a non-hospital pharmacy from the beginning. Make sure that you tell your doctor and your pharmacist which other drugs you are taking, to avoid drug interactions. Who will pay ? Antiretroviral drugs are free, whether or not you are "100% covered" by the Sécurité Sociale as an HIV-positive person. You will not need to pay anything if you are entitled to the Sécurité Sociale benefits. In hospitals and outside, you do not need to pay anything, the pharmacist will be reimbursed directly by the "assurance maladie". Anyone residing in France is entitled to "assurance maladie" or "aide médicale". This also applies to foreign nationals living in France, regardless of their administrative circumstances. If you are not registered under "Sécurité Sociale", ask your town hall ("mairie") or a hospital for a "service social". Doctors and social workers ("assistantes sociales") are available in "Consultations précarité", which exist in many hospitals; these can be attended by persons without any official documentation. Make sure your rights are respected Whether in town or in a hospital, you are entitled to confidentiality and discretion. If you are not pleased with a pharmacy, feel free to go to another one. As with doctors you may need to try several ones before you find the one you feel comfortable with. If you, or anyone you know, meets with difficulties while the double dispensation system is being set up, please let AIDES or Remaides know about it. Setting up a new system clearly means that there will be a learning curve. Even though efforts have been made to anticipate problems, oversights or loopholes will certainly be found. Let us be alert and bring these problems to the attention of the Government so that we get the quality service we are entitled to. Jérôme SOLETTI
In town and in the hospital, you will be able to choose your pharmacy A double " Sécurité sociale" card If you request it, the "caisses primaires d'assurance maladie" (CPAM) are under the obligation of providing you with a copy of the " Sécurité sociale" card which does not indicate any confidential information, in particular the one dealing with a 100% reimbursement of expenses ("exonération du ticket modérateur"). This has been published in the "Bulletin Officiel" : "circulaire" CNAMTS/DGR n°98-95 dated 28 September 1995, "circulaire" DGS/DSS/DH/DAS n°97/166 dated 4 march 1997, and published in the "Bulletin Officiel" n°97.12 dated 26 April 1997. Where can you have your viral load measured ? Up to now, viral load could only be measured in a hospital. Starting in October, private analyses laboratories should be able to perform this test. This will be entirely free (or reimbursed) for HIV-positive persons, as are anti-HIV drugs and other "classical" blood tests. However, before this is officially implemented, it is preferable to continue having this test performed in a hospital to make sure that its cost is covered. Later on, all non-hospital laboratories should be able to perform viral load tests. They will undergo quality control inspections by the Health Ministry to ensure that this test is performed under optimal safety and reliability conditions. |