Newsline

1. Delays in obtaining care pose risks to patients and community
2. Prophylaxis following sexual exposure to HIV
3. CD4 count and viral load do predict progression in pediatric patients
4. Reinfusion of autologous CD8 cells

Delays in obtaining care pose risks to patients and community

Counseling is essential to ensure that newly diagnosed patients begin therapy promptly

In most cases, valuable treatment time has already been lost by the time someone receives a diagnosis of HIV infection. The challenge for care providers who communicate an HIV diagnosis is to help patients recognize the importance of avoiding further delays in obtaining treatment, where immediate treatment is warranted. According to one recent study, the delay between initial diagnosis of HIV infection and the first clinical visit can be significant -- and these long delays may seriously alter an individual's disease course.

Samet et al. followed 189 patients with HIV infection who were seen at Boston City Hospital or Rhode Island Hospital between February 1994 and April 1996. These patients had received a diagnosis of HIV infection at some point in the past and were presenting for their first primary-care visit pursuant to that diagnosis. The median delay between diagnosis and first primary-care visit was three months, with the mean delay being 24 months. Fully 39% of the cohort waited longer than one year to make their first visit; 32% waited more than two years; and 18% did not seek primary care for more than five years after their initial diagnosis. At presentation, the median CD4 count was 280 cells/mm³. Exposure to HIV occurred by intravenous drug use in 43%, heterosexual transmission in 37%, and male-male sexual activity in 20% of the participants, the majority of whom were non-white.

The authors used two statistical analyses to determine characteristics that may have contributed to delays in seeking primary care. In a bivariate analysis, the following factors were found to be significant: male sex, living in a residence for less than six months, prior jail time, no living mother, no spouse or partner, not being aware of HIV status at time of testing, and being notified of HIV status by telephone or mail.

Several of these factors also emerged as significant contributors to delay when a multivariate linear regression model was used to examine the data. These factors were: history of IV drug use, no living mother, not being aware of HIV status at time of testing, and being notified of HIV results by mail or telephone.

Aside from the obvious harm patients may suffer by delaying antiretroviral or prophylactic therapy, Samet et al. point out, there are serious public-health issues that providers should also consider when they are encouraging HIV-infected patients to seek the care they need. Prevention of tuberculosis transmission is one such objective (see "Predictors of TB infection," Vol. 3, No. 5). Prophylactic use of AZT in HIV-positive women who become pregnant is another, because its use is associated with decreased vertical HIV transmission (see "AZT Diminishes Transmission of HIV-1 from Mothers to Their Infants," Vol. 1., No. 2, pages 31-35). The authors note that effective treatment of other STDs in patients who have been diagnosed with HIV but have not elected to begin treatment may decrease the transmission of HIV, and they encourage all care providers to avail themselves of the opportunity to help drug-using patients obtain treatment for their addiction.

Samet JH, Freedberg KA, Stein MD, Lewis R, Savetsky J, Sullivan L, et al. Trillion virion delay. Arch Intern Med 1998; 158: 734-740.

Dr. James O. Kahn, a member of the editorial advisory board of HIV Newsline, comments:

This study casts a pall over recent efforts to simplify HIV testing and the process by which individuals are notified of test results. When the patients surveyed by Samet et al. received their diagnosis by mail or telephone, they were markedly less likely to seek primary care in a timely manner. This is hardly a surprise -- there is no replacement for compassionate, straightforward, face-to-face counseling when a diagnosis of this magnitude is communicated to a patient. Indeed, this moment, difficult as it is, provides us with an opportunity to emphasize how effective current treatments are in arresting the insidious advance of HIV infection, and it allows us to assess how ready a particular patient is to begin treatment.

Except in cases of primary HIV infection or well-advanced, life-threatening disease, it is rarely necessary to begin anti-HIV therapy immediately. Whenever possible, I actually encourage patients to postpone the initiation of therapy for several weeks. This gives them a chance to accommodate themselves to their diagnosis and prepare themselves for the restrictions and rigors of multidrug therapy.

There is all the difference in the world, of course, between an interval of several weeks and a hiatus of several years. The first is often prudent; the second is always unwise. As this study makes abundantly clear, delays in seeking treatment may have dire consequences not just for a patient's prognosis but for the overall health of the community as well. Samet et al. identify a number of factors that should help physicians identify individual patients who may be reluctant to initiate the care they need. Their findings underscore how critical it is that counseling be incorporated into every discussion of HIV-test results.

Prophylaxis following sexual exposure to HIV

Treat within 72 hours, especially if risk of infection is high

There is good evidence that antiretroviral drugs can decrease the likelihood of HIV infection following occupational exposure, and prophylaxis is routinely offered in this setting (see "Reducing the Risk of Occupational Exposure to HIV," Vol. 1, No. 4, pages 69-73, and "New data on workplace exposure to HIV: ZDV prophylaxis reduces risk of infection by 81%," Vol. 4, No. 2). What about prophylaxis following sexual exposure? Should physicians offer the equivalent of "morning after" pills to people who believe they have been exposed to HIV through sexual activity?

Katz and Gerberding tackle this complex question in a rational and cogent "Perspective" article in a recent issue of The Annals of Internal Medicine. Their overall recommendation is to treat people who have reason to believe they have been exposed to HIV within the previous 72 hours. Going further, they suggest a comprehensive primary-care approach to patients in this situation. The first step is to assess the incident by obtaining a detailed description of the mode of exposure and by determining the following:

• Presence of factors that could influence transmission (STDs, genital ulcers, etc.)

• Other contributing factors (broken condoms, substance use)

• Use of contraception by heterosexual couples

• HIV status of partner; if positive, clinical status and treatment history

• Previous high-risk behavior of presenting patient

The authors recommend prophylaxis for patients who have engaged in unprotected receptive or insertive anal or vaginal intercourse, and for those who report unprotected receptive fellatio with ejaculation (if the patient's partner was likely to be HIV-positive). In addition, patients who have used HIV-infected needles or other drug paraphernalia should be treated.

The recommended treatment regimen is ZDV and 3TC for four weeks. Alternatively, d4T and ddI can be used for the same length of time, although ZDV is the only drug for which post-exposure efficacy data are available. It may be prudent to add a protease inhibitor if the source partner has advanced disease, is known to have a very high viral load (>50,000 copies/mL), or if he or she has been treated with nucleoside analogs. The authors recommend indinavir or nelfinavir. Routine use of a third drug is likely to increase the incidence of adverse events and will complicate compliance, however. In addition to prophylaxis, Katz and Gerberding suggest routine laboratory tests and assessment for other STDs such as hepatitis, gonorrhea, syphilis, and chlamydia. When appropriate, vaccinations for hepatitis A and B should be offered. Patients should be counseled about safer-sex practices and told to be on the lookout for symptoms of acute HIV infection.

The authors acknowledge that the public perception that a safe and effective "morning after" treatment for HIV exposure now exists will greatly complicate safer-sex educational initiatives. This is clearly an issue that needs to be addressed head-on. Anticipating the irresponsible patient who habitually practices unsafe sex and routinely presents for post-exposure prophylaxis, they concede that these patients must be treated. However, such patients obviously need other interventions, such as counseling and/or substance-abuse treatment.

Katz MH, Gerberding JL. The care of persons with recent sexual exposure to HIV. Ann Intern Med 1998; 128 (4): 306-12.

CD4 count and viral load do predict progression in pediatric patients

Viral load above 100,000 copies/mL mandates a change in therapy

For a variety of reasons, most of the clinical studies conducted in the early years of the AIDS epidemic were open only to adults. As a result, we often had a good idea of how adults would respond to a particular drug or drug combination long before we had any data on how pediatric patients responded to these treatments. During this period those who provided care to infants, toddlers, and preadolescents with HIV disease were often obliged to extrapolate standards of care and parameters of success or failure from data gathered in trials that involved no children.

Fortunately, the F.D.A. now routinely approves the use of new antiretroviral drugs in pediatric patients -- if the pharmacokinetic data are available in children and efficacy has been shown in adults. Furthermore, a new F.D.A. regulation will require that all new drugs be studied simultaneously in adults and children.

For these young patients and their care providers, a recent report in The Pediatric Infectious Disease Journal sheds some much-needed light on the thorny question of how to predict disease progression in children. For two years, a team of researchers from Duke University followed 86 children with HIV. Over the course of the study 22 of these children developed an AIDS-defining illness or died.

The Duke team reports that CD4 cell count and viral load proved to be reliable predictors of disease progression in these pediatric patients. Children who began the study with low CD4 counts and high viral loads were at much greater risk of developing AIDS: 92% of those with CD4 counts below 5% and viral loads above 100,000 developed C.D.C.-defined AIDS or died after an average of 179 days, while only 4% of the children with CD4 counts above 15% and viral loads below 100,000 progressed to AIDS.

Valentine ME, Jacobson CR, Vavro C, Wilfert CM, McClerren D, St Clair M, Katz SL, McKinney RE. Evaluation of surrogate markers and clinical outcome in 2-year followup of 86 HIV-infected pediatric patients. Ped J Infect Dis 1998; 17: 18-23.

Dr. Catherine M. Wilfert, a principal author of this report and a member of the editorial advisory board of HIV Newsline, comments:

Based on what we now know about disease progression in adults with HIV, the fact that low CD4 counts and high viral loads put pediatric patients at high risk of disease progression comes as no surprise. This study and several others have finally provided us with benchmark CD4 and HIV RNA values to predict disease progression in children. Normal CD4 counts are considerably higher in infants and toddlers than they are in adults, and those normal values change as young children grow up. This means that the guidelines for when to initiate treatment or begin prophylaxis that are based on adult CD4 counts are not applicable to younger patients.

Interpreting viral-load levels in children is even more difficult, chiefly because the values are so high in infants and decline very slowly in the first years of life. After establishing the value of CD4 cell counts and viral-load measurements as surrogate markers of disease progression in children with HIV, my colleagues and I were also able to suggest tentative treatment guidelines for young patients with HIV disease. Our data, which complement those of other investigators, suggest that a viral load above 100,000 copies/mL in a child with HIV disease mandates a change in therapy.

Reinfusion of autologous CD8 cells

Experimental technique seems to improve immunologic parameters

Although dramatic advances in antiretroviral therapy have become commonplace in the last two years, efforts to repair severely damaged immune systems in people with HIV infection have borne little fruit to date. Experimental approaches include manipulation of chemical messengers, such as interleukin-2, which stimulate and cause proliferation of specific immune-system cells. Other researchers have tried harvesting certain types of cells from people with HIV, inducing proliferation in vitro, and reinfusing these "expanded" populations of cells into the same donor. Trickett et al. report their experience with a variation of the latter approach.

In recognition of the role that CD8 cells, also known as cytotoxic T-lymphocytes, or CTLs, play in suppression of HIV, this group removed native CTLs from 12 patients with HIV infection and cryopreserved them. The cells were not expanded or manipulated in any way after they were harvested. The autologous CTLs were thawed and reinfused into the same donor at some point over the observation period to assess whether this therapy would alter the course of infection in participants. Reinfusions took place over a period of time ranging from seven to 41 months post-harvest. Although mostly consisting of CD8 cells, the cryoprecipitate also included CD4, NK, B cells, and monocytes.

All participants were asymptomatic at the time of cell harvest, with 10/12 classified as having C.D.C.-defined Stage II disease. The remaining two subjects were Stage III at baseline. CD8 counts were at least 1,000 cells/mm³ at enrollment. The majority had CD4 counts greater than 200 cells/mm³ and 2/12 had counts in the 300-cell range. Autologous cells were reinfused when CD4 counts showed a decline on at least two occasions a month or more apart or dropped below 200 cells/mm³. (For those with baseline values below 200 cells/mm³, a consistent decline was considered adequate justification for reinfusion.) No adverse reactions to the infusions were reported.

A number of immunologic and virologic parameters improved following receipt of autologous CD8 cells. CD4 counts showed a mean increase of 25% at two weeks, but this improvement was sustained for more than one month only in the patients with baseline values in the 300-cell range. In most patients, CD8 cells showed a slower decline following treatment. Again, the two patients with higher CD4 cells at baseline demonstrated enhanced responses, with increases in CD8 cells that were sustained for six months. Two patients with detectable p24 antigen at entry experienced a 50% decline in p24 levels for at least three months. Likewise, HIV RNA declined by more than 0.5 log in three of the four patients for whom frozen plasma was available for testing. While several of the patients initiated antiretroviral therapy with nucleoside analogs during the trial, these patients did not receive infusions of CD8 cells for two to six months after initiating treatment. The authors assert that the improvements in immunologic and virologic parameters seen several weeks after patients received infusions are more likely to have been associated with the cell transfer than with antiretroviral therapy begun months before.

This small study suggests that autologous transfusions of CD8 cells may play a role in restoring immune competence in patients with HIV infection who are experiencing deterioration in parameters of immune function. The method these investigators employed, which did not involve expansion of cell lines, is advantageous for two reasons: it simplifies the procedure, and it removes an intervention that may be ineffective or have unintended effects.

Trickett AE, Kelly M, Cameron BA, Lloyd A, French RA, Dwyer JM. A preliminary study to determine the effect of an infusion of cryopreserved autologous lymphocytes on immunocompetence and viral load in HIV-infected patients. J AIDS 1998; 17: 129-136.