Two examples from the field of infectious diseases in the past year demonstrate the increasing role of nontraditional forms of communicating medical information. First, a report in the New York Times (1) described isolation of the SEN virus, which is a proposed cause of transfusion-associated hepatitis not attributable to known agents and may account for many cases of unexplained chronic liver disease. The virus was discovered at a biomedical research center in Italy and has not been described in the medical literature because of a pending patent. The investigator was advised by corporate lawyers that he had to wait a full year before submitting a detailed scientific report on the virus, including evidence of causality. Second, the Internet is increasingly being used to present timely and clinically relevant information, which ultimately may be peer-reviewed and appear in print. A recent example is a meta-analysis of studies from the past three decades on the antibiotic treatment of sinusitis (2).

Antimicrobial Resistance

Penicillin has been available for more than five decades. When it was introduced, nobody anticipated what we see today: the considerable problem of penicillin-resistant Streptococcus pneumoniae. This illustrates the difficulty inherent in predicting when and where resistance will emerge. Pneumococcal resistance was first noted in the late 1970s and by 1997–1998 affected 16% to 18% of Streptococcus pneumoniae strains. These figures refer to strongly resistant strains; the rates would be substantially higher if strains with intermediate resistance were included. Only high-level resistance is relevant in nonmeningeal pneumococcal infections. The importance of this issue is clear when it is recognized that pneumococcus is still the major pathogen identified in patients with pneumonitis, exacerbations of bronchitis, and sinusitis. In a seeming paradox, the Centers for Disease Control and Prevention (CDC) recommends ß-lactams as the preferred drugs for penicillin-resistant pneumococcal infection because strains with intermediate resistance are vulnerable to antibiotic levels readily achieved with oral amoxicillin (and also with ceftriaxone or cefotaxime). The number of resistant strains will probably continue to increase; at some point, it is conceivable that penicillin may no longer be used to treat pneumococcal infection.

Nearly One Third of Streptococcus pneumoniae Strains Were at Least Partially Resistant to Penicillin

Doern GV, Brueggemann AB, Huynh H, et al. Antimicrobial resistance with Streptococcus pneumoniae in the United States, 1997-98. Emerg Infect Dis. 1999; 5:757-65.

The so-called SENTRY study analyzed antimicrobial resistance patterns for 1601 clinical isolates of Streptococcus pneumoniae taken from consecutive patients at 34 medical centers in the United States. In all, 29.5% of isolates were at least partially resistant to penicillin, and 12.1% were fully resistant. Overall rates of intermediate- or high-level penicillin resistance at the participating centers ranged from 13% to 65%. Approximately 5% of isolates exhibited multidrug resistance; they were not susceptible to penicillin and two or more other non–ß-lactam antibiotics. Resistance rates were 4% for ceftriaxone, 13% for tetracycline, and an alarming 20% for trimethoprim–sulfamethoxazole. Penicillin resistance was most prevalent in isolates from middle-ear fluid and sinus aspirates from young children and ambulatory care patients. In 19 of 24 centers that took part in a similar study 3 years earlier (3), rates of penicillin resistance had increased by 3% to 39%. Resistance to other agents increased comparably during this time. Rifampin, trovafloxacin, quinupristin–dalfopristin, and vancomycin proved active against more than 99% of penicillin-resistant isolates.

Streptococcus pneumoniae Has Become Progressively Less Susceptible to Fluoroquinolones in Canada

Chen DK, McGeer A, de Azavedo JC, et al. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. Canadian Bacterial Surveillance Network. N Engl J Med. 1999; 341:233-9.

This survey from the Canadian Bacterial Surveillance Network tested 7551 Streptococcus pneumoniae isolates for reduced susceptibility to ciprofloxacin (the only available fluoroquinolone), defined as a minimum inhibitory concentration of 4 µg/mL or higher. Between 1988 and 1997, prescriptions for fluoroquinolones increased from 0.8 to 5.5 per 100 persons each year. At the same time, the rate of reduced susceptibility to fluoroquinolones increased from 0% in 1993 to 1.7% in 1997–1998 (2.9% in adults). Persons 65 years of age or older received fluoroquinolones relatively often and were most vulnerable to fluoroquinolone resistance, which was associated with penicillin resistance.

The fluoroquinolones, along with quinupristin–dalfopristin and vancomycin, are prime candidates for use in areas of high penicillin resistance or for patients so ill that no chance of resistance can be risked. Fluoroquinolones are now heavily promoted for use against all pneumococcal infections; in Canada, about 5% of all persons have received a prescription for a fluoroquinolone. It should be noted that another recent report, from Canada, examined resistance in nearly 1200 Streptococcus pneumoniae isolates obtained in 1997–1998 at centers in 9 of the 10 provinces (4) and showed that more than 99% of Streptococcus pneumoniae strains were susceptible to fluoroquinolones. Whether these drugs should be restricted out of concern over developing resistance or are a reasonable option for serious pneumococcal infection remains debatable. Few organisms are currently resistant to these drugs, and resistance is not developing to an alarming degree; nevertheless, there is cause for concern.

Bacteremia

In contrast to pneumococcal disease, which is largely community-acquired, bacteremia is mostly a nosocomial infection. A survey by the CDC, covering the years 1995 to 1997, examined blood cultures in patients in 49 hospitals throughout the United States who were thought to have clinically significant bacteremia (5). The most common offender, constituting 32% of bacteremic infections, was Staphylococcus epidermidis, followed by Staphylococcus aureus (16%) and enterococcus (11%). These findings contrast with the situation in the 1970s and 1980s, when gram-negative bacteria were the predominant cause of bacteremia. Contrary to what many expected, the major pathogens today are gram-positive cocci, rather than gram-negative rods such as Pseudomonas or Enterobacter species. Methicillin-resistant Staphylococcus aureus is endemic in most U.S. hospitals, and about one in five nosocomial enterococcal isolates is resistant to vancomycin (6). Vancomycin resistance is transferable from enterococci to Staphylococcus aureus. This observation is worrisome because although enterococcus has no defined virulence factor, Staphylococcus aureus is a vicious pathogen capable of causing serious infections. Staphylococcus aureus with intermediate resistance to vancomycin was reported in Japan in 1996, and since then four such strains have been isolated in the United States. They are defined by a minimum inhibitory concentration for vancomycin of 8 to 16 µg/mL. Three of the four U.S. patients from whom strains were isolated had end-stage renal disease and had received long-term vancomycin treatment (7). Resistance in these cases is not explained by the usual mechanism in which the vancomycin A, B, or C plasmid is transferred from the enterococcus. These cases, although few, have profound public health implications.

Treatment Recommendations

The new CDC 12-step program, described by Gerberding (8), is an organized protocol for dealing with antibiotic-resistant infection in hospitalized patients. The first step is to remove catheters, a major factor in bacteremia. Cultures are also a priority, permitting pathogen-specific treatment. The CDC, as well as some major third-party payers, strongly endorses the concept of online drug ordering to avoid errors. Other facets of the program are performance feedback—for informed as well as questionable decisions. The recommendations also advocate aggressive treatment with the goal of eradicating the infecting microorganism. Clinicians should avoid vancomycin when possible. They should take care not to overtreat Staphylococcus epidermidis, which is a contaminant about 50% of the time when recovered in blood cultures and probably is the most overtreated organism. Finally, handwashing for 30 seconds must not be forgotten.

Numerous new antibiotics have recently been introduced to deal with resistant organisms. In addition to the new fluoroquinolones are the ketolide antibiotics. Quinupristin–dalfopristin is available in hospital pharmacies, and linezolid has recently been approved by the U.S. Food and Drug Administration (FDA). The major antibiotic-resistant offenders among gram-positive cocci are methicillin-resistant Staphylococcus aureus, glycopeptide- or vancomycin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant pneumococci. Most of these resistant strains are susceptible to linezolid and to quinupristin–dalfopristin. Both are very expensive.

A major challenge in dealing with antibiotic resistance is to curtail the abuse of these drugs. The CDC and other groups are developing recommendations for treating respiratory tract infections—the occasion for about 70% of all antibiotic use in the United States—with the intent of decreasing the number of antibiotic-resistant infecting organisms.

Pharyngitis

The CDC guidelines for pharyngitis in children stipulate that treatment be limited to patients with a positive culture or positive result on an antigen assay for group A streptococcus.

Sinusitis

It has proven difficult to determine whether sinusitis in a given case is a result of bacterial infection and to determine who should be treated. Most cases are viral infections, and most of the bacterial infections clear spontaneously. As a result, many patients are treated so that a few will benefit. Treatment decisions probably will rest mainly on clinical severity and possibly on the duration of infection. A meta-analysis of nearly 50 studies reported from 1969 to 1999, comprising approximately 5000 patients, showed no antibiotic to be better than amoxicillin (2). This meta-analysis, however, does not take into account the recent reports of increasing resistance. Treatment did appear to speed recovery, and clinical judgments were as reliable as conventional radiography or computed tomography. The latter reportedly demonstrates sinusitis in about 80% of all persons who have a cold that lasts longer than 48 hours, but these patients do well without receiving antibiotics (9). Orbital and central nervous system complications are rare; none were encountered in this large series.

Bronchitis and Pneumonia

Acute bronchitis is not an indication for antibiotic treatment, with the possible exception of pertussis. Many studies confirm that patients whose cough and purulent sputum result from acute viral bronchitis do not benefit from antibiotics. Many authorities recommend that exacerbations of chronic bronchitis be treated with antibiotics if two of three cardinal symptoms are present: cough, fever, and sputum production. Pneumonia is treated with antibiotics if a pulmonary infiltrate is documented.

Community-Acquired Pneumonia

Critical Pathway Made the Hospital Treatment of Community-Acquired Pneumonia More Efficient

Marrie TJ, Lau CY, Wheeler SL, et al. A controlled trial of a critical pathway for treatment of community-acquired pneumonia. CAPITAL Study Investigators. Community-Acquired Pneumonia Intervention Trial Assessing Levofloxacin. JAMA. 2000; 283:749-55.

Unlike many pathway studies, this one used a unique format by randomly assigning 19 hospitals, rather than wards or patients, to use of a critical pathway or conventional management. The pathway group used the Pneumonia Severity Index described by Fine and colleagues (10) to determine the need for hospitalization. Outpatients received oral L-floxacin, 500 mg/d for 10 days, and hospital patients received the same dosage intravenously starting within 4 hours of presentation. Oral treatment was substituted when fever was controlled, blood cultures were negative, vital signs were normal, and the patient could eat. Hospital discharge with a prescription for oral treatment was recommended for patients in the pathway group when the leukocyte count was less than 12 000 cells/mL and the oxygen saturation exceeded 90%. Analysis of 1743 patients showed that the critical pathway reduced the average length of hospital stay from 6.1 to 4.4 days (P = 0.04) and reduced the admission rate among low-risk patients by 18% (P = 0.01). In addition, the duration of intravenous therapy declined an average of 1.7 days. Nearly two thirds of patients treated according to the pathway but only 27% of controls received a single class of antibiotics. Mortality, complications, quality-of-life ratings, and readmissions did not differ between the two groups.

In this trial, probably one of the most important pneumonia studies in many years, use of a critical pathway reduced adverse outcomes and saved, on average, an estimated $1700 per patient. Time to initiation of treatment is a crucial variable. The standard of care today is to treat within 8 (preferably 4) hours after presentation, which often means starting treatment in the emergency department. Although some practitioners, including me, prefer to individualize treatment, almost all studies of pathways show that they perform better than standard care, regardless of the antibiotic chosen. It seems likely that pathways will be increasingly used and that their rules will become standards of care for which clinicians will be audited.

Selected Antibiotic Regimens Decreased Short-Term Mortality in Hospitalized Elderly Patients with Community-Acquired Pneumonia

Gleason PP, Meehan TP, Fine JM, et al. Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia. Arch Intern Med. 1999; 159:2562-72.

A retrospective review of nearly 13 000 hospital records for Medicare patients with pneumonia attempted to relate 30-day mortality to initial antimicrobial therapy, using as a reference standard single-agent therapy with a second- or third-generation cephalosporin (ceftriaxone, cefotaxime, or cefuroxime). Just over one fourth of the patients received such treatment. Compared to the reference standard, the combination of a cephalosporin and macrolide reduced 30-day mortality by 26% (odds ratio for death, 0.74), and treatment with a fluoroquinolone alone reduced it by 36% (odds ratio, 0.64). In contrast, use of a ß-lactam–ß-lactamase inhibitor plus a macrolide was independently associated with higher 30-day mortality, as was a combination regimen that included an aminoglycoside. Overall 30-day mortality was 15.3%. As expected, a direct correlation was found between risk for death and the severity of illness. The investigators concluded that older patients hospitalized with pneumonia do best when given a regimen active against the most common "typical" pathogens, such as Staphylococcus pneumoniae and Haemophilus influenzae, as well as "atypical" pathogens, such as Mycoplasma pneumoniae and Chlamydia pneumoniae.

This study has influenced the revised guidelines for treating community-acquired pneumonia developed by the Infectious Diseases Society of America, which recommends empirical treatment of pneumonia with a fluoroquinolone alone or a macrolide combined with ceftriaxone or cefotaxime. The reason these regimens proved superior in Gleason and colleagues' study is not well understood. Some authors believe that atypical organisms may be unexpectedly important pathogens (or co-pathogens), a situation that may merely reflect geographic or seasonal variation. Another possibility is that, at a time of increasing ß-lactam resistance, the fluoroquinolones and macrolides are simply more effective against pneumococcal pneumonia. The anti-inflammatory action of macrolides may be part of the explanation. There is legitimate concern that the fluoroquinolones will be used excessively for community-acquired pneumonia and promote resistance by Streptococcus pneumoniae. However, this is unlikely if their use is limited to patients with community-acquired pneumonia because the average U.S. physician sees only two or three such patients each year.

Infections New and Old

West Nile Virus Confirmed as Cause of an Encephalitis Outbreak in the New York City Region

Lanciotti RS, Roehrig JT, Deubel V, et al. Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States. Science. 1999; 286:2333-7.

The West Nile virus, classified as a flavovirus, is transmitted by birds and mosquitos; humans, along with dogs and horses, are accidental hosts. Seroprevalence rates exceeding 90% are reported from Egypt, Africa, and Israel. Only 1 in 300 infected persons develops symptoms such as fever, weakness, and myalgias after an incubation period of 2 to 6 days. Leukopenia is characteristic. West Nile virus infection may be diagnosed by detecting IgM antibody or analyzing cerebrospinal fluid for the virus by using polymerase chain reaction. No treatment is available, making it necessary to rely on mosquito control for prevention.

The first cases in the United States were found in 1999 by Dr. Deborah Asnis at Flushing Hospital Medical Center in Queens, New York. Serologic findings in the six affected patients initially suggested St. Louis encephalitis; at about the same time, however, a fatal form of encephalitis was discovered in birds at the Bronx Zoo and was identified correctly as West Nile virus infection. Ultimately, 62 cases and 7 deaths from West Nile virus infection were confirmed in New York City in 1999.

Lanciotti and colleagues' report describes a complete genomic analysis of the initial isolate from an infected flamingo at the Bronx Zoo. The investigators positively identified West Nile virus after doing a phylogenetic analysis of the E-glycoprotein gene for related viral isolates obtained from mosquitos and two fatal human cases. The North American strain was closely related to West Nile virus isolated from a dead goose in Israel in 1998. Only 2 nucleotide differences were found in more than 12 000 nucleotides analyzed, compared to 37 nucleotide differences between the New York agent and the West Nile virus strain isolated in Romania in 1996. No human cases have been reported from Israel, and it remains unclear how the virus was introduced into the United States. An earlier report in The Lancet described the use of oligonucleotide primers hybridizing to conserved regions of flavoviruses to sequence a Kunjin/West Nile–like flavovirus (one of the Japanese encephalitis group) in the brains of patients with New York encephalitis (11).

Experience with the West Nile virus in the United States exemplifies the unpredictability of infectious diseases. It is also a reminder that these infections may be imported by international travelers or borne by infected imported food or animals (in this case, illegally imported birds are suspected). More cases of West Nile encephalitis are expected because the virus has been isolated in a bird and in mosquitos in the New York City region in 2000 (indicating that the virus survived the winter). Measures to prevent breeding of mosquitos are the best public health strategy for controlling the disease.

Oral Neuraminidase Inhibitor Limited Viral Shedding and Symptoms in Experimental Human Influenza

Hayden FG, Treanor JJ, Fritz RS, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. JAMA. 1999; 282:1240-6.

The CDC epidemic report (11) showed that 1999 was a bad year for influenza, the third year running that the Sydney strain of influenza A (H3N2) has dominated influenza in the United States. The neuraminidase inhibitors, zanamivir and oseltamivir, were introduced this past influenza season as new agents for treating infections caused by influenza A and B. Hayden and colleagues evaluated the new orally active agent, oseltamivir, for prevention and treatment of influenza A/Texas/39/91 (H1N1). Their two randomized, double-blind, placebo-controlled trials isolated 117 healthy adults aged 18 to 40 years (all of whom were serologically susceptible) in hotel rooms and inoculated them intranasally. Participants in the prevention study received oseltamivir, 100 mg once or twice daily, or a matching placebo, starting 26 hours before viral inoculation. The treatment study used 20, 100, or 200 mg of oseltamivir twice daily or 200 mg once daily, starting 28 hours after viral challenge. All regimens were continued for 5 days, and participants remained isolated for 8 days after inoculation. In the prevention study, 67% of placebo recipients and 38% of persons given oseltamivir became infected, for an efficacy of 61%. Only 6 of 12 placebo recipients shed virus. One third of the placebo group but no one in the oseltamivir group had infection-related respiratory illness (P 01). In the treatment study, symptom scores were significantly lower in the oseltamivir group (P 0.05) and nasal washings contained lower levels of inflammatory cytokines. Oseltamivir caused more cases of mild to moderate nausea, which could be prevented by taking the drug with food.

In these studies, symptoms were controlled about 1 to 1.5 days sooner in participants given oseltamivir, and the benefit was especially noticeable in those who were more ill. To put these results in context, amantadine and rimantadine are active only against type A, whereas both neuraminidase inhibitors are active against type B as well. All these agents have similar therapeutic effectiveness and all have prophylactic value, although the neuraminidase inhibitors have not been approved by the FDA for prophylactic use. Amantadine may cause severe central nervous system side effects; the adverse effects of rimantadine are less severe. Zanamivir, when inhaled in aerosol form, can cause cough and bronchospasm. Oseltamivir produces gastrointestinal side effects in 10% to 20% of patients. To be effective in acute infections, all these drugs must be given within 48 hours of symptom onset; unfortunately, many patients are not seen soon enough. The FDA has issued warnings that zanamivir may cause wheezing and that with either neuraminidase inhibitor a bacterial superinfection may go undetected and untreated.

Long-Term Follow-up of Young Adults Infected by Hepatitis C Virus Suggested That the Outlook May Be Less Grim Than Previously Thought

Seeff LB, Miller RN, Rabkin CS, et al. 45-year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med. 2000; 132:105-11.

An estimated 4 million Americans (2% of the population) and 100 million persons worldwide are probably infected with hepatitis C virus (HCV). Infection is chronic in approximately 85% of patients, and about 20% of patients with hepatitis C develop cirrhosis within 20 years; far fewer patients develop hepatocellular carcinoma. With use of interferon and ribavirin, a sometimes punishing regimen, about 30% of patients in the United States with HCV genotype I (the dominant form) are cured, and perhaps two thirds of those with the less common genotypes do well.

In a long-term follow-up study, Seeff and colleagues examined the natural history of HCV infection, which is important in determining who should be treated. They analyzed sera that had been obtained from about 8500 military recruits from 1948 to 1954 for analysis of group A streptococcal infections and acute rheumatic fever. Seventeen of these recruits (0.2% of the study sample) had HCV antibody. During follow-up that lasted up to 45 years, 2 of these men (12%) developed liver disease, and 1 (6%) died of liver disease. Among 8551 HCV-seronegative controls, 119 (1.4%) died of liver disease. The investigators concluded that HCV infection may be less ominous over the long term than has generally been thought.

Although some patients with hepatitis C will benefit from treatment, decisions should be tempered by the prospect of significant side effects and a recognition that most infected persons have a good long-term outlook. In addition, treatment is costly and protracted. Studies that support the observations by Seeff and colleagues are life-table analyses showing that survival curves for patients with transfusion-associated HCV infection and patients who underwent transfusion without becoming infected can nearly be superimposed on one another (13). The two main factors that promote faster progression are alcoholism and co-infection with HIV.

Carefully Controlled Study Showed That Chronic Symptoms Were Not Very Frequent 4 Years after a Diagnosis of Lyme Disease

Seltzer EG, Gerber MA, Cartter ML, et al. Long-term outcomes of persons with Lyme disease. JAMA. 2000; 283:609-16.

This report from the "home" of Lyme disease describes a community-based longitudinal cohort study of 678 patients randomly chosen from among residents of Connecticut who, from 1984 to 1991, were suspected of having Lyme disease. Interviews were completed with 212 patients and the same number of age-matched controls without Lyme disease. Nearly two thirds of patients in the larger series met national criteria for Lyme disease, and about 85% received antimicrobial therapy. Erythema migrans was completely specific for Lyme disease. Facial palsy, arthritis, and carditis had intermediate specificity in this respect (50% to 66%). None of the 29% of patients who presented with nonspecific symptoms proved to have Lyme disease. After average follow-up of 4 years (maximum follow-up, 11 years), patients in the cohort did report more pain, fatigue, and difficulty with daily activities than controls, but the difference was fully explained by patients who did not meet the case definition. Between 11% and 21% of both groups described joint swelling, headaches, memory loss, fatigability, difficulty in exercising, and trouble sleeping.

There is little question that some patients with Lyme disease do have recurrent arthritis and other late complications, but these complications are relatively rare. In addition, patients are not more disposed than other persons of the same age to have chronic, nonspecific symptoms. These findings bring into question the assumption that such symptoms result from persistence of the organism after inadequate treatment. The long-term prognosis of Lyme disease, given appropriate treatment, seems to be good.

HIV Infection

The most dramatic change in this field is the improvement in outcome since protease inhibitors were introduced in late 1995. The CDC data for 1996–1998 showed a 75% decrease in mortality and comparable declines in the rates of AIDS-defining opportunistic infections, HIV-related hospitalizations, and perinatal transmission.

Guidelines

The redefined International AIDS Society–USA guidelines for antiretroviral agents (14) recommend initiating therapy when the viral load exceeds 30 000 HIV RNA copies/mL or the CD4 count is less than 350 cells/mm³. For initial treatment, the recommendation is for two nucleoside analogues combined with one or two protease inhibitors or a non-nucleoside reverse transcriptase inhibitor.

Heterosexual Transmission Probably Correlated with Viral Load

Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med. 2000; 342:921-9.

In this excellent study, Quinn and colleagues followed 415 discordant Ugandan couples for up to 30 months to discern the correlation between viral load and other factors with risk for HIV transmission. Laboratory testing and interviews conducted at regular intervals indicated that, contrary to previous studies in the United States, female-to-male transmission was about as efficient as male-to-female transmission. Much of this difference could be attributed to circumcision: Seroconversion never occurred in 50 seronegative men who had been circumcised. Viral load played the expected critical role in risk; the virus was not transmitted when the load was less than 1500 HIV RNA copies/mL. The odds ratio for transmission was 1.0 with a viral load of 1500 to 3500 HIV RNA copies/mL, 6.3 with a load of 3501 to 50 000 HIV RNA copies/mL, and 11.9 when the load exceeded 50 000 HIV RNA copies/mL. These findings are expected because the efficiency of transmission of nearly any infectious disease is known to be largely a function of the size of the inoculum. These data, coupled with previous reports of perinatal transmission and the experience with HIV transmission in occupational exposures, show that viral load in the source is a critical factor. Nevertheless, HIV-infected persons lacking detectable virus should not be assured that they cannot transmit HIV. Evidence suggests that the virus can endure in genital secretions even when it is not detected in the blood, so that the risk in that situation is low, but not zero (15).

The "Berlin Patient": What Happened?

The famous "Berlin patient," arguably the best known of HIV-infected patients, presented with the acute retroviral syndrome, a viral load of 80 000 to 90 000 HIV RNA copies/mL, and a CD4 count of 370 cells/mm³. He was treated with didanosine, hydroxyurea, and indinavir, then withdrew from treatment three times; the first two interruptions were followed by a viral rebound, but the third was not. The patient has now gone longer than 19 months without therapy. The most recent reports indicate that the Berlin patient has a viral load less than 20 HIV RNA copies/mL, a CD4 count of 783 cells/mm³, and a normal CD4–CD8 ratio. The virus remains present in his CD4 cells and lymph nodes, but circulating virus is not detected. Strong HIV-specific CD4 responses and a strong CD8 cytotoxic lymphocyte response were documented (16). The current interpretation is that the patient was "vaccinated" at the time of the rebound and was eventually able to control the virus after a second "vaccination" when treatment again was stopped. Experience with this patient suggests that although cure of HIV infection is not a realistic possibility, it may be feasible to "train" a patient's immune system to control the virus so that disease will not progress, in a manner that may be analogous to the immune control achieved by long-term nonprogressers. "Structured treatment interruptions" are now being used as a tactic to achieve immune control of HIV. Findings to date shows that therapy may be interrupted at least five times without development of viral resistance. The approach seems sound, but the Berlin patient is the only described patient who actually has achieved control over his own virus.

Single-Dose Nevirapine Prevented Perinatal HIV Transmission More Efficiently Than a Multidose Zidovudine Regimen

Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet. 1999; 354:795-802.

This comparative study randomly assigned more than 600 HIV-infected pregnant women to receive 200 mg of nevirapine at the onset of labor (infants also received 2 mg/kg of body weight within the first 3 days of life) or 600 mg of zidovudine orally when labor began, followed by 300 mg every 3 hours until delivery (infants received 4 mg/kg orally twice a day for 1 week). The placebo group was dropped early in the course of the study. Transmission of HIV was apparent in offspring at 14 to 16 weeks in 21.5% of the zidovudine group and 13.1% of the nevirapine group, nearly a 50% reduction (P < 0.001). Serious maternal side effects occurred in 4% to 5% of both groups, and treatment-related complications also were comparably frequent in the two infant groups. Nevirapine would seem to be an excellent drug for preventing perinatal transmission, and it may also be a good choice for health care workers who are exposed to HIV-1.

HIV Resistance

The original report on transmission of a resistant strain of HIV (17) described a patient with an acute retroviral syndrome. Transmission of a resistant strain was confirmed by the finding that all resistance mutations in the HIV strain isolated from the source patient were also present in the sexual contact. The strain was resistant to multiple reverse-transcriptase and protease inhibitors. Resistant mutations occur in an estimated 5% to 10% of newly infected patients, and that proportion is expected to increase. Many authorities now believe that resistance testing is appropriate for patients with acute retroviral infection and when salvage treatment is planned. The data are then used to design a treatment regimen. Factors contributing to resistance include partial suppression due to nonadherence to treatment, vagaries in pharmacokinetics, drug interactions, marginal potency, and other considerations that are as yet poorly understood. The drugs used today are less likely to be effective a few years hence because of escalating resistance, mirroring experience with antibacterial agents.

Nationwide Survey Found That HIV Infection Clusters in Men, Black Persons, and the Poor and That Patients Are Still Undertreated

Bozzette SA, Berry SH, Duan N, et al. The care of HIV-infected adults in the United States. HIV Cost and Services Utilization Study Consortium. N Engl J Med. 1998; 339:1897-904.

The HIV Cost and Services Utilization Study, which sought to understand how HIV-infected patients are cared for in the United States, had randomization at three levels: throughout the country by metropolitan and rural areas, among physicians within these areas, and among patients within physician practices. Three fourths of the sample of 4042 HIV-infected adults were interviewed in early 1996. Some of the major findings were as follows:

1. It is estimated that fewer than half of the 650 000 to 900 000 HIV-infected adults receive medical care, defined as one visit at least every 6 months. Most patients receiving treatment have advanced disease.

2. HIV infection is found disproportionately in men, black persons, and the poor.

3. Only 10% of patients receiving care have CD4 cell counts consistently exceeding 500 cells/mm³.

4. About 85% of adults thought to have AIDS have received antiretroviral therapy.

5. The direct cost of care averages approximately $20 000 per patient per year. The total cost of caring for HIV-infected adults in the United States accounts for less than 1% of all direct personal health expenditures.

Despite expressed concern by the authors that uninsured persons are deprived of access to quality health care, 80% of patients lacking health insurance have received treatment with drugs that cost $10 000 to $20 000 per year. The main reason for this record is the Ryan White CARE (Comprehensive AIDS Resource Emergency) Act, which funds much of the drug therapy and outpatient care in the United States.