INTRODUCTION

The natural history of HIV infection and its clinical manifestations in adolescence are not yet fully understood. Adolescents who become infected through sexual contact or through injecting drugs appear to follow a clinical course more similar to that of adults than to that of children. On the other hand, adolescents infected through vertical or parenteral transmission in childhood have a unique clinical course, different from other adolescents and long-term adult survivors. Currently, the majority of infected adolescents contracted HIV through sexual contact and are in relatively early stages of infection, determining the unquestionable importance of prevention in this age group. We have found, however, a significant minority of patients who reach adolescence in advanced stages of the disease, whether from vertical, sexual or parenteral transmission.

Clinical experience with protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) is limited in adolescents. Therefore, current recommendations for the treatment of HIV infection and opportunistic infections in adolescents should be based on Tanner pubertal staging, rather than chronological age. Thus, adolescents in the early stages of puberty (Tanner I-II) should follow the recommendations of the pediatric consensus, while those in advanced stages of sexual maturation (Tanner V) should follow the recommendations of the adult consensus. In the intermediate stages (Tanner III and IV), treatment should be individualized, at the physician’s discretion and closely monitored to assess dosage adequacy, toxicity, and efficacy.

INITIAL MEDICAL EVALUATION

There are no defined standards for the routine evaluation of adolescents with suspected HIV. An evaluation over several visits is recommended, which should be as complete as possible, including medical history, review of systems, physical examination, and routine laboratory tests, in addition to psychosocial assessment and information on the different aspects and implications of HIV infection, including pre- and post-test counseling. It is essential to establish a relationship of trust between the doctor and the patient, and whenever possible, the family should be involved in this process. A multidisciplinary approach is also important. Serious social problems are often encountered, such as having both parents HIV-positive or having one or both parents orphaned. Due to the complexity of the antiretroviral procedures available today and the fundamental role of adherence to treatment for therapeutic success, the role of a multidisciplinary approach cannot be overlooked.

LABORATORY EVALUATION

Laboratory tests in adolescents are similar to those performed in adults. It should be noted that the normal values ​​of some laboratory tests in adolescence differ from those in adults (e.g., alkaline phosphatase is increased during the growth spurt, but may also indicate liver infiltration by tuberculosis, Mycobacterium avium complex [MAC], or cytomegalovirus [CMV]) and even between the sexes (e.g., higher hemoglobin in boys).

Laboratory tests can be divided into general and specific. Specific tests are those that assess immune function and the prognosis for disease progression, as well as therapeutic response. These include the CD4+ cell count (T helper lymphocytes) and their ratios, and quantification of viral load (copies of viral RNA per milliliter of plasma).

In short, the main target of HIV infection is the cells of the immune system, mainly CD4+ lymphocytes. Every day, from the onset of infection, billions of viral particles (on the order of 1 to 10 billion) are produced and an equal number of CD4+ cells are infected and destroyed. There is a reasonable correlation between the number of virions produced in the various compartments of the body and the quantity of viral particles in the blood (viral load). Over the years, a true erosion of the immune system occurs, and after about seven to ten years, when T lymphocyte levels fall to less than 200 cells/mm3 ⁽ on average), clinically manifest AIDS results. Thus, the CD4+ lymphocyte count provides information about the patient’s current immunological status in the spectrum of the disease and the viral load provides information about the prognosis of the disease. John Mellors (1997) showed, in a study carried out in the 1980s, the combined value of CD4 and viral load in the prognosis of evolution over three years. The Table shows the relevant information pertinent to the viral load.

Patients with high CD4+ counts (above 750 cells/mm3 ⁾ can develop AIDS in a short period of time (32.6% in three years if the viral load is above 55,000 copies/ml versus 0% if below 500 copies). On the other hand, patients with CD4+ counts below 200 cells/mm3 ^, but with relatively lower viral loads (7,000 to 20,000 copies/ml), developed AIDS in only 8.1% of cases in three years.

The significance of CD4+ and viral load can be metaphorically compared to a locomotive moving towards a cliff. CD4+ would represent the distance remaining to travel to the cliff, and viral load, the speed at which the locomotive is moving. Thus, by treating the infection and reducing the viral load, we are keeping the locomotive moving as slowly as possible towards the cliff. Whether we can stop the locomotive or even make it run backwards is not yet clear. The evidence suggests that it is possible to keep the locomotive stopped at least for a while. New work showing evidence of immune reconstitution suggests that it may be possible to make it run backwards.

INDICATIONS FOR ANTI-RETROVIRAL TREATMENT

Medical treatment of HIV infection is based on scientific principles, which can be summarized as follows:

• viral replication leads to immune system damage and progression to AIDS. HIV infection is always harmful, and long-term survival free of immune dysfunction is rare;
• plasma viral load levels indicate the magnitude of HIV replication and the associated rate of immune cell destruction, while CD4+ cell levels show the extent of damage the immune system has already suffered. Regular and periodic measurement of viral load and CD4+ cells is necessary to determine the risk of progression in an HIV-infected patient and to determine when to initiate or modify antiretroviral regimens;
• as progression rates differ between individuals, treatment decisions should be individualized by risk status as indicated by plasma viral load and CD4+ cell levels;
• the use of potent antiretroviral combinations to suppress viral replication below the detection limit (of currently available laboratory methods) reduces the potential for selection of HIV variants resistant to these antiretrovirals, which are the main limiting factor in the ability of antiretrovirals to inhibit viral replication and prevent disease progression. Therefore, the goal of therapy should be to achieve the maximum possible suppression of viral replication;
• the most effective way to achieve long-lasting suppression of HIV replication is to use combinations of effective anti-HIV drugs simultaneously with which the patient has not been previously treated and which do not have cross-resistance with drugs used in the past;
• each antiretroviral drug used in combination therapy must always be used according to the best possible dosage regimen and with maximum adherence (there are studies showing that the best results are achieved when adherence is 95% or more);
• the number of antiretroviral drugs available is limited in number and mechanism of action, and cross-resistance between specific drugs has been documented. Therefore any change in antiretroviral therapy increases the possibility of future therapeutic limitations;
• Women should receive antiretroviral therapy at the usual doses regardless of whether they are pregnant or not. Options should be discussed with patients and therapeutic decisions should be individualized;
• the same principles of antiretroviral therapy apply to children, adolescents and adults, although the treatment of HIV-infected children involves unique pharmacological, virological and immunological considerations;
• People with acute primary HIV infection should be treated with combination antiretroviral therapy to suppress viral replication below the detection limits of currently available methods;
• HIV-infected individuals, even those with viral loads below detection limits, should be considered infectious and advised to avoid drug use and sexual behaviors that are associated with the transmission or acquisition of HIV and other infectious pathogens.

It is beyond the scope of this article to go into the detailed pharmacology of the drugs currently available to treat HIV infection. Briefly, there are three classes of drugs used to treat HIV infection (a new class of drugs, fusion inhibitors, was recently added to the therapeutic arsenal, the representative of which is enfuvirtide. However, production is limited and this drug is not available on the national market). The first class is the nucleoside analogue reverse transcriptase inhibitors (NRTIs), which, as the name suggests, mimic nucleosides that are used to construct nucleic acid. HIV, being a retrovirus, uses an enzyme called reverse transcriptase to transcribe viral RNA into DNA, which is incorporated into the host cell, which serves as a matrix for the production of new proviruses. These drugs enter the DNA chain and block the action of the enzyme, which cannot use them in DNA synthesis. There are currently eight drugs available on the market in this class (AZT, DDI, DDC, D4T, 3TC, abacavir, tenofovir and emtricitabine, the latter two of which are not available in Brazil), with different toxicities and varying degrees of cross-resistance within the class. The second class is the NNRTIs, which inhibit the same enzyme but by a direct mechanism, different from that described above. These drugs, three of which are currently available on the market (nevirapine, delavirdine and efavirenz), have the limitation of having virtually complete cross-resistance to each other and of HIV becoming resistant with just one mutation in reverse transcriptase. The third class of drugs is represented by protease inhibitors, a viral enzyme necessary for viral maturation. Inhibition of this enzyme produces viral particles with no infectious capacity. There are currently seven drugs on the market belonging to this class (saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir and atazanavir, the latter not available in Brazil), with different degrees of toxicity and the disadvantage of having a high potential for cross-resistance among them.

The specific doses and side effects of each drug will not be discussed here, nor will the opportunistic infections related to HIV infection or their prophylaxis and treatment. Nor will specific situations such as the treatment of pregnant women infected with HIV or post-exposure prophylaxis be addressed. The objective of this article is to provide the reader with a general approach to the patient and to inform him/her of the current state-of-the-art in treatment. The reader can find excellent reviews and official recommendations on these subjects on the websites www.aids.gov.br, www.cdc.gov, www.natap.org, www.aidsinfo.nih.gov, www.hopkins-aids.edu, www.unaids.org and www.prn.org.

CONCLUSIONS

AIDS is an infectious disease that has assumed catastrophic proportions, especially in Third World countries. According to data from the World Health Organization (WHO) from December 2002, there were approximately 42 million infected people worldwide at the time, of which 3.2 million were children. Approximately 50% of adults were female. There were 3.2 million deaths (610,000 were children) that year alone. It is worth remembering that, although 90% of AIDS patients are in the Third World, 90% of the money spent on medication is on the 10% of patients who live in the First World. In other words, only 10% of the world’s infected population has access to antiretroviral medication.

It is clear that, for a disease with these characteristics, the main strategy is prevention through global campaigns and the development of an effective vaccine. However, to date, there is no vaccine with proven efficacy in clinical use. Furthermore, it is worth remembering that the annual expenditure on vaccine research does not reach 10% of the expenditure on research into new drugs. Studying vaccines is complicated in a disease with a slow clinical progression for which there is no good animal model.

The most effective remedy is therefore prevention, which necessarily involves massive and ongoing education. The AIDS prevention program in Thailand, which since the early 1990s has developed a massive information campaign and encouraged condom use, has shown that, through pragmatic and objective actions, it is possible to drastically reduce the incidence and prevalence of the infection. South Africa, on the other hand, has moved in the opposite direction. The delay in recognizing the emerging infection and the importance of prevention campaigns has meant that this country, with just over 40 million inhabitants, is now home to the largest number of AIDS cases in the world in absolute numbers (around 10% of the population). In addition to the difficulty in changing behavior, since habits do not change overnight, there are also economic and cultural barriers. In some countries, even strong religiosity is a barrier to prevention. In Brazil, the largest Catholic nation in the world, for example, the Catholic Church is against any method of birth control and the use of condoms for any purpose. This is undoubtedly yet another barrier to any government campaign for condom use.

Most people are intelligent enough to understand what AIDS is and the role of male (or female) condoms in preventing sexual transmission (the method of transmission in about 90% of cases). Sex, however, is not an exercise in intellectual activity. Neither is brushing your teeth. People do not brush their teeth simply because they have concluded that food debris between the teeth causes cavities. They brush their teeth every day because it is a habit acquired from an early age, just like taking a shower, not throwing trash on the floor, being polite in traffic, etc. There are several studies in countries such as the United States showing that young people who receive sex education in school more often choose to delay the onset of sexual activity and use condoms in their relationships compared to those who do not receive it. Detractors of these campaigns that encourage the use of condoms claim that this type of information encourages sex among young people. It is a medieval attitude to believe that well-informed people are less able to prevent themselves. Finally, it is worth quoting a phrase from the writer, playwright and cartoonist Millôr Fernandes: “Using a condom means never having to ask for forgiveness”.