Editorials

Acute HIV-1 Infection: Early Identification and Treatment

MARTIN MARKOWITZ, M.D.
Rockefeller University
New York, New York

In this issue of American Family Physician, Perlmutter and colleagues¹ carefully discuss the diagnosis and treatment of persons newly infected with human immunodeficiency virus (HIV-1). Certain aspects of this topic merit additional comment.

See article in this issue.

As clinicians, our first responsibility in assessing the acutely ill patient is to diagnose life-threatening conditions and initiate appropriate therapy. However, acute HIV-1 infection is not life-threatening. Nevertheless, failure to consider the diagnosis makes it impossible to order the definitive diagnostic laboratory tests--plasma HIV-1 measurements and HIV-1 serologies.² Without the results of these specific tests, the clinician will not be able to make the proper diagnosis, raising many questions.

Does a failure to consider an HIV diagnosis compromise our patients' future clinical course? Furthermore, do we compromise their future clinical course by failing to promptly identify the pathogen and initiate appropriate antiviral therapy? Or, are we exposing these patients to therapies with significant short- and long-term toxicities without clear evidence of long-term benefit? Moreover, will early intervention even endanger the future therapeutic response in these patients if a drug-resistant virus develops as a result of intermittent adherence to treatment?

Failure to identify a patient who is newly infected with HIV-1 may result in a permanently lost opportunity. Current guidelines support early treatment based on virologic, immunologic and public health considerations.³ Rosenberg and co-workers⁴ have demonstrated that treating primary HIV-1 infection allows for the maintenance of T-helper cell responses to HIV-1­specific antigens, whereas these responses are more difficult to demonstrate in similarly treated, chronically infected persons. Given the knowledge that a small, slowly decaying latent infectious reservoir is established very early in the course of HIV-1 infection, the maintenance of these immune responses may be critical if the ultimate goal of immune control of HIV-1 is to be achieved.

Why are these immune responses thought to be so critical? Perhaps, the characterization of patients with long-term HIV-1 infection and the absence of immunologic progression (long-term non-progressors [LTNPs]) has given us a clue to the importance of HIV-1­specific immune responses. These patients as a group are characterized by high levels of CD4 cell proliferation to HIV-1­specific antigens and robust HIV-1­specific cytotoxic T cell responses, as well as a modest viral burden.^5,6 Although LTNPs make up at most only 5 percent of the HIV-1­infected population, they have provided us with an important model which may be achieved with early intervention.⁷

Based on a series of interventional clinical trials that provided insight into HIV-1 replication dynamics in vivo, a two-compartment model of HIV-1 replication was proposed in which some infected cells decay rapidly (half-life of one day) and some decay slowly (half-life of two to four weeks).^8,9 We hypothesized that if virus replication could be completely suppressed and no other compartment exists, then HIV-1 would be "eradicated" in 30 to 36 months of continuous antiretroviral therapy. However, with the identification of a longer-lived latent population (minimal half-life of six months), eradication with antiviral therapy alone becomes less likely.¹⁰

Nevertheless, early therapy can clearly limit the size of this latent pool by controlling the repetitive rounds of virus replication characterizing the chronic asymptomatic phase of HIV-1 infection. We have recently demonstrated that early therapy can result in profound suppression of virus replication and preservation of the host immune system.¹¹ Also, hypothetically, the long-term results of this suppression are unknown but, with therapy, less virus and more potent immune responses may allow for subsequent immune control of HIV-1 infection.

The public health consequences of undiagnosed HIV-1 infection are significant. Despite reductions in HIV-1­associated morbidity and mortality,¹² new infections continue to occur at alarming rates, particularly in adolescents and women. Failure to inform patients that they may transmit this infection either sexually or through intravenous drug use can only further aggravate this trend. Though immediate diagnosis does not guarantee responsible behavior, early initiation of therapy and reductions of viremia to extremely low levels will likely reduce transmissibility of the pathogen.

Early therapy has risks as well as benefits. The toxicities of therapy along with the complexity of the current regimens make patient adherence a critical issue. Intermittent pill-taking may result in the emergence of drug-resistant variants.¹³ However, even though the current therapies have a long way to go before they can be considered "ideal," withholding therapies because of these considerations abolishes the benefit of early diagnosis and treatment.

Untreated HIV-1 infection is characterized by high-level ongoing virus replication that ultimately results in immunodeficiency. The therapeutic advances in the past five years have clearly made it possible to reduce and maintain viral replication to minimal levels. The prospect of achieving a virologic remission (that is, control of replication in the absence of antiviral therapy) remains a daunting challenge. However, if this goal is to be achieved, the newly infected patient with a minimally impaired immune system and a minimal viral burden is certain to be the most likely successful candidate.

Dr. Markowitz is assistant professor at Rockefeller University and clinical director of Aaron Diamond AIDS Research Center, New York, N.Y.

Address correspondence to Martin Markowitz, M.D., Rockefeller University, New York, N.Y. 10016.

REFERENCES

1. Perlmutter BL, Glaser JB, Oyugi SO. How to recognize and treat acute HIV syndrome. Am Fam Physician 1999;60:535-46.
2. Schacker T, Collier AC, Hughes J, Shea T, Corey L. Clinical and epidemiologic features of primary HIV infection. Ann Intern Med 1996;125:257-64.
3. Carpenter CC, Fischl MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, et al. Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA Panel. JAMA 1998;280:78-86.
4. Rosenberg E, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, Walker BD. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 1997;278:1447-50.
5. Pantaleo G, Menzo S, Vaccarezza M, Graziosi C, Cohen OJ, Demarest JF, et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Eng J Med 1995;332: 209-16.
6. Cao Y, Qing L, Zhang LQ, Safrit JT, Ho DD. Virological and immunological characterization of long-term survivors of HIV-1 infection. N Engl J Med 1994;332:201-8.
7. Haynes B, Pantaleo G, Fauci AS. Toward an understanding of the correlates of protective immunity to HIV infection. Science 1996;271:324-7.
8. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995;373:123-6.
9. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life span, and viral generation time. Science 1996;271:1582-6.
10. Perelson A, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K, et al. Decay characteristics of HIV-1 infected compartments during combination therapy. Nature 1997;387:188-91.
11. Markowitz M, Vesanen M, Tenner-Racz K, Cao Y, Binley JM, Talall A, et al. The effect of commencing combination antiretroviral therapy soon after human immunodeficiency virus type 1 infection on viral replication and antiviral immune responses. J Infect Dis 1999;179:527-37.
12. Palella F, Delaney K, Moorman A, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced HIV infection. N Engl J Med 1998;338: 853-8.
13. Deeks SG, Hecht FM, Swanson M, et al. HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban AIDS clinic: response to both initial and salvage therapy. AIDS 1999; 13:F35-42.

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The Conundrum of Early HIV Infection

JAY SIWEK, M.D.
CLARISSA C. KRIPKE, M.D.
Georgetown University Medical Center
Washington, D.C.

On the surface, it seems reasonable to advise physicians to suspect early human immunodeficiency virus (HIV) infection when clinically indicated and to be prepared to intervene with antiretroviral therapy. However, this premise is fraught with pitfalls and challenges for physicians on the front lines of care.

See article in this issue.

Exactly who should be tested, and when? If physicians only test the highest-risk patients, the majority of patients with early HIV infection will be missed. Risk factors do not reliably discriminate between those who might be infected and those who are not infected.

A single episode of unprotected sexual intercourse might transmit HIV infection--just ask all of the young adults who have become infected without having multiple sexual partners. In fact, the highest rates of new infections are in patients who do not fall into easily defined high-risk groups. Almost any person who has been sexually active is at risk. Thus, when confronted with a person in whom early HIV infection is a possible diagnosis, the burden appears to rest on the clinician to prove that HIV is not the cause of the patient's symptoms--which brings up the next dilemma.

The symptoms of early HIV infection mimic those of many common benign viral illnesses,¹ and it is not possible to reliably exclude HIV infection as a possible cause on clinical grounds alone. There is no practical way to routinely and confidently exclude early HIV infection as a cause of common viral syndromes.

To put things into perspective: let us say that a physician practices in a college student health clinic. During the week, the physician sees dozens of students with infectious syndromes, ranging from the common cold, to influenza, to mononucleosis, to nonspecific viral illness. Many of these students will be sexually active, which makes them at risk for HIV infection. (Just think of all of the other sexually transmitted diseases that are routinely seen in a college clinic--chlamydia, herpes, trichomonas, papillomavirus, and so forth.)

So, what is the physician to do? If no such student is tested for early HIV infection, cases will be missed. On the other hand, routinely testing all students also presents many difficulties. First, because it is too early for HIV antibody to form, costly viral RNA testing must be done. Then, there is the anxiety created for students awaiting their test results. Imagine walking into a physician's office for what you thought was a bad cold and learning that you may actually have HIV infection! Students coming in for cold symptoms would have to receive an extended counseling session before testing, and many would need a second appointment to deliver the results. Multiplying that scenario many times each year could easily overwhelm an office's resources.

Is this scenario plausible? Absolutely. In a recent study, researchers evaluated serum samples for evidence of acute HIV infection from patients who were being tested for infectious mononucleosis. Approximately 1 percent of the patients in this study had unrecognized acute HIV infection.² Considering this degree of risk of a fatal disease, the argument could be made that most sexually active patients who are tested for mononucleosis should be tested for acute HIV infection if they are heterophile-negative. This strategy is not yet standard practice today.

However, physicians should gradually become more liberal in testing for early HIV infection. Currently, we do so somewhat arbitrarily, by making educated guesses rather than by being systematic. However, we should move toward testing more routinely. We must develop rapid test kits that will give readings in the office and work to overcome the technical and financial challenges that prevent us from optimizing HIV diagnosis and treatment. As discussed in the article by Perlmutter and colleagues,³ the goal is for clinical practice to keep up with the many advances in diagnosing and treating early HIV infection.

Dr. Siwek is chair of the Department of Family Medicine at Georgetown University Medical Center, Washington, D.C. He is also editor of American Family Physician. Dr. Kripke recently completed a medical editing fellowship with American Family Physician.

Address correspondence to Jay Siwek, M.D., Department of Family Medicine, Georgetown University, 212 Kober-Cogan Hall, Washington, D.C. 20007.

REFERENCES

1. Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med 1999; 339:33-9.
2. Rosenberg ES, Caliendo AM, Walker BD. Acute HIV infection among patients tested for mononucleosis (letter). N Engl J Med 1999;340: 969.
3. Perlmutter BL, Glaser JB, Oyugi SO. How to recognize and treat acute HIV syndrome. Am Fam Physician 1999;60:535-46.

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Current Trends in Cervical Ripening and Labor Induction

BARBARA S. APGAR, M.D., M.S.
University of Michigan Medical School
Ann Arbor, Michigan

In recent years, there has been recognition that if the cervix is unfavorable, labor will rarely progress successfully to a vaginal delivery. Bishop attempted to define parameters of successful or failed labor induction with a cervical scoring system. Successful outcomes of cervical ripening include vaginal delivery without prolonged labor times, no increase in infection rates and good neonatal outcomes. Although the Bishop score is widely accepted, and it is agreed that progressive cervical dilatation will rarely occur unless softening and distensibility occur first, the task of "motivating" the cervix to achieve an optimal Bishop score has been challenging and frustrating.

See article in this issue.

What is the most optimal cervical ripening agent? The safety profile, efficacy and cost should figure into the decision analysis as each agent is compared in a randomized, controlled study. Although an effective labor-inducing agent, oxytocin (Pitocin) has not proved to be the best cervical ripening agent. Mechanical devices, various prostaglandin preparations, and local application of estrogen and relaxin are currently vying to be the cervical ripening agent of choice.

Prostaglandin E₂ (PGE₂) analogs have been widely studied. The only currently available PGE₂ analog labeled by the U.S. Food and Drug Administration (FDA) for use in cervical ripening is dinoprostone, marketed as a gel (Prepidil) for intracervical administration and as a timed-release vaginal insert (Cervidil). Despite widespread use of dinoprostone, randomized trials have failed to validate that its use results in a reduced cesarean section rate despite its benefits as a cervical ripening agent.¹

However, there is a better and less costly cervical ripening agent available, although the FDA has not yet labeled it. Misoprostol (Cytotec), an E₁ prostaglandin, has been labeled for the treatment and prevention of gastric ulcer disease associated with the use of nonsteroidal anti-inflammatory agents, but it has not been labeled for use in obstetric applications. The efficacy, safety and cost-effectiveness of misoprostol for cervical ripening and labor induction have been validated by numerous randomized, controlled trials. Compared with intracervical PGE₂ gel, vaginal misoprostol has shown efficacy in reducing time to delivery and increasing the probability that vaginal delivery will occur within 24 hours of initiation of the drug without need for oxytocin augmentation.² Misoprostol has also been shown to be an effective alternative to oxytocin infusion for labor induction in women with premature rupture of the membranes at term.³

A meta-analysis⁴ of eight randomized trials assessing the safety and efficacy of misoprostol for cervical ripening and labor induction in 966 women (488 of whom received misoprostol and 478 of whom served as control subjects) confirmed the impact of its use. All of the patients in the control groups received PGE₂ or oxytocin, with the exception of one trial in which patients were given placebo. The dosage of misoprostol varied from 25 µg every two hours to 100 µg as a single dose. Six trials included use of continuous fetal electronic monitoring and tocodynamometry.

Compared with patients in the control groups in these studies,⁴ patients receiving misoprostol had lower cesarean section rates as well as shorter durations of labor and reduced need for oxytocin augmentation. No differences were noted in the incidence of low five-minute Apgar scores and neonatal intensive care admissions. Although the rate of tachysystole was two times higher in the groups receiving misoprostol, compared with the control groups, the difference was not statistically significant. There have been no documented studies validating that tachysystole with use of misoprostol results in adverse outcomes in mother or fetus. Although meta-analyses provide evidence of statistical differences in the effectiveness of various drugs, they do not replace the results of a large randomized trial.⁴ Large studies are currently under way in several institutions.

Using off-label drugs in obstetrics such as those used to arrest preterm labor is not uncommon. Clinicians must be aware of the pitfalls when these drugs are used. Just because a drug is used for an off-label indication does not imply that it is experimental and that sufficient studies have not been conducted. Wing and Paul,⁵ authors of numerous articles on cervical ripening agents, have suggested guidelines for the use of misoprostol. Hospital protocols should be formulated and adherence to inclusion and exclusion criteria, and surveillance of outcomes should be strictly encouraged. Informed consent should be obtained after the options for cervical ripening and labor induction are discussed. A note should be written stating that the risks and benefits of the drug have been explained and that consent has been given to use it for a particular situation.

The authors stress that it is extremely important for the 100 µg tablet of misoprostol to be carefully cut into quarters by the pharmacist to ensure correct dosing.⁵ A 25-µg dose every four hours appears to be the optimal dosage to induce labor and avoid adverse events. The quartered tablet is placed directly into the posterior vaginal fornix, preferably without the use of lubricant, which can interfere with absorption and dissolution of the tablet. The authors' protocol does not recommend misoprostol use for longer than 24 hours. If oxytocin augmentation is required, it should be given no sooner than two hours after the last dose of intravaginal misoprostol.

The authors' guidelines for redosing misoprostol state that it should be withheld if two or more contractions occur in 10 minutes, a Bishop score of 8 has been achieved, active labor begins or the fetal heart rate pattern is nonreassuring.⁵ If uterine tachysystole (defined as six or more contractions in a 10-minute window for two consecutive 10-minute windows) occurs, 0.25 mg of terbutaline (Bricanyl) should be administered subcutaneously.

Wing and Paul⁵ have laid out a reasonable protocol that maximizes the effectiveness of misoprostol while minimizing adverse events. Physicians electing to use misoprostol for labor induction and cervical ripening should follow published guidelines and should be able to confidently manage adverse events.

Dr. Apgar is clinical associate professor in the Department of Family Medicine at the University of Michigan Medical School in Ann Arbor. She is also an associate editor of American Family Physician.

Address correspondence to Barbara S. Apgar, M.D., M.S., Chelsea Family Practice Center, University of Michigan, 14700 E. Old U.S. 12, Chelsea, MI 48118.

REFERENCES

1. Keirse MJNC. Prostaglandins in preinduction cervical ripening: meta-analysis of worldwide clinical experience. J Reprod Med 1993;38:89-100.
2. Chuck FJ, Huffaker BJ. Labor induction with intravaginal misoprostol versus intracervical prostaglandin E₂ gel (Prepidil gel): randomized comparison. Am J Obstet Gynecol 1995;173:1137-42.
3. Wing DA, Paul RH. Induction of labor with misoprostol for premature rupture of membranes beyond thirty-six weeks' gestation. Am J Obstet Gynecol 1998;179:93-9.
4. Sanchez-Ramos L, Kaunitz AM, Wears RL, Delke I, Gaudier FL. Misoprostol for cervical ripening and labor induction: a meta-analysis. Obstet Gynecol 1997;89:633-42.
5. Wing DA, Paul RH. Misoprostol for cervical ripening and labor induction: the clinician's perspective and guide to success. Contemp Ob/Gyn 1999;44: 46-61.

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