Update in Infectious Diseases

General Topics

Deaths from Infection Are on the Upswing

Pinner RW, Teutsch SM, Simonsen L, Klug LA, Graber JM, Clarke MA, et al. Trends in infectious diseases mortality in the United States. JAMA. 1996; 275:189-93.

At the beginning of the 20th century, infectious diseases were by far the most common cause of death. By mid-century, however, advances in the prevention and management of these diseases were dramatic enough to raise hopes that infectious diseases would cease to be a significant cause of death by the century's end. The opposite, however, seems to be the case.

To evaluate recent trends in mortality from infectious diseases in the United States, Pinner and colleagues studied International Classification of Diseases, Ninth Revision (ICD-9) codes from the National Center for Health Statistics for 1980 through 1992. They focused on codes for underlying causes of death that exclusively represent infectious diseases. Some infection-related diseases were analyzed separately because recent studies had implicated a microbial cause. Examples of the latter are peptic ulcer disease (Helicobacter pylori), cervical carcinoma (human papilloma virus), nonalcoholic cirrhosis, and hepatocellular carcinoma (hepatitis B and C viruses).

During the 13-year study period, the rate of death from infectious diseases increased from 41 per 100 000 persons to 65 per 100 000 persons, an increase of 58% (Table 1). The rate increased 6.3-fold for persons 25 to 44 years of age, primarily because of the acquired immunodeficiency syndrome (AIDS). However, the rate of death from infections increased 25% for persons 65 years of age and older, and the rate of death from septicemia increased 83%. Collectively, infectious diseases were the third leading cause of death in 1992. Of those deaths, 47% were caused by infections of the respiratory tract, 20% by AIDS, 11% by septicemia, and 7% by infections of the urinary tract.

Public health policy during the past two decades has been largely based on the downward trends noted in the early 1900s. The upward trend in the rate of death from infections is currently being addressed by the emphasis placed on “emerging infections” by the U.S. Centers for Disease Control and Prevention (CDC), the Institute of Medicine, and other groups. Focal emerging infections include the hantavirus pulmonary syndrome, Lyme disease, Ebola virus infection, and infection with “flesh-eating” streptococcus. To keep things in perspective, however, nearly half of the deaths from infection in the United States were caused by respiratory infections, most were in persons older than 65 years of age, and most were categorized as caused by “pneumonia of unspecified etiology.”

Eradication of Measles in the Americas

de Quadros CA, Olive JM, Hersh BS, Strassburg MA, Henderson DA, Brandling-Bennett D, et al. Measles elimination in the Americas. Evolving strategies. JAMA. 1996; 275:224-9.

Measles is a potentially eradicable disease that as late as 1980 was one of the three most common fatal infections in the world. The World Health Organization estimates that worldwide, more than 1 million children die of measles each year. The measles vaccine has been available since 1963 and entered widespread use in the United States in the late 1970s. The Pan American Health Organization has made the elimination of measles a high priority.

The report by de Quadros and colleagues reviews the Pan American Health Organization's method for rapidly interrupting the transmission of the measles virus through mass campaigns for routinely vaccinating infants. The program begins with a “catch-up” phase that includes a one-time initial vaccination of all children who are 9 months to 14 years of age, regardless of vaccination history, within 1 to 4 weeks. The second stage is the “mop-up” vaccination campaign in areas of low coverage. The third stage involves routine immunization to ensure that all new birth cohorts of children receive measles vaccination at 12 to 15 months of age. The follow-up period is characterized by periodic vaccination campaigns in preschool children; these campaigns were developed because results of serologic tests showed that these children have levels of susceptibility that exceed the threshold.

Since 1991, all countries belonging to the Pan American Health Organization except Canada and the United States have launched catch-up measles vaccination campaigns, and many have successfully completed the entire menu of measles elimination. A review of the experience of 15 countries shows that 93% of 146 million children have been vaccinated. Transmission of the measles virus seems to have been successfully interrupted in Cuba, Chile, and some Central American countries.

This report shows that regional measles elimination is possible, a finding that may set the stage for eventual global eradication of measles. It also shows that immunization rates of 100% are not necessary to eradicate diseases. Usually, a immunization rate of 80% to 85% provides sufficient “herd immunity” to deprive an infectious pathogen of an effective means of spread.

Influenza Vaccination for Working Adults Saves Money

Nichol KL, Lind A, Margolis KL, Murdoch M, McFadden R, Hauge M, et al. The effectiveness of vaccination against influenza in healthy, working adults. N Engl J Med. 1995; 333:889-93.

While much attention is being devoted to epidemics of “emerging infections,” the most fatal epidemic infection in the United States receives little public attention. That “invisible” infection is influenza, which accounts for 10 000 to 40 000 deaths per year. An estimated 150 000 influenza-related hospital admissions occur each year, costing $12 billion annually. Nichol and colleagues sought to determine the cost-effectiveness of influenza vaccination for healthy adults.

The study was a randomized, controlled trial of employed, healthy adults 18 to 64 years of age. In 1994, the participants were recruited at work sites, at shopping malls, and through newspapers announcements. The 849 participants were randomly assigned to receive either vaccination or placebo. Their health status was monitored during the influenza season (December through March) through telephone interviews. Primary study outcomes included upper respiratory illnesses, absenteeism from work because of these illnesses, and visits to physicians' offices for these illnesses. The economic benefits of vaccination were analyzed by estimating the direct and indirect costs associated with immunization and with upper respiratory illnesses.

Persons who received vaccine reported 25% fewer upper respiratory illnesses than those who received placebo (105 episodes per 100 persons compared with 140 episodes per 100 persons; number needed to treat [NNT] to prevent one episode, 2.9), 43% fewer days of sick leave from work due to these illnesses (NNT to prevent a lost day of work, 1.9), and 44% fewer visits to physicians' offices for these illnesses (NNT to prevent a visit, 4.2). The cost savings were estimated to be $46.85 per person vaccinated.

The conclusion of this study-that vaccination against influenza has substantial health-related and economic benefits for healthy, working adults-is probably valid. However, because the attack rate in the 1994-1995 influenza season was higher than average, the cost savings in other years may not be as great. Another study showed a cost savings of $1.10 to $6.11 in elderly and high-risk patients, but it measured only direct health costs [1]. When all costs are accounted for, it seems clear that influenza vaccination is a cost-saving procedure.

Prognosis for Multidrug-Resistant Tuberculosis Can Be Improved

Park MM, Davis AL, Schluger NW, Cohen H, Rom WN. Outcome of MDR-TB patients, 1983-1993. Prolonged survival with appropriate therapy. Am J Respir Crit Care Med. 1996; 153:317-24.

In the United States, the incidence of and mortality from tuberculosis decreased throughout most of the 20th century until the late 1970s, when both reached a plateau (Figure 1). The goal of eradicating tuberculosis by the year 2000 is now unlikely to be met, and the United States must acknowledge tuberculosis as a continuing serious disease. The steady decline in the rate of tuberculosis was reversed in the mid-1980s, and the rate in New York City has since more than doubled [2]. The reasons are complex and include the HIV epidemic, the substance abuse epidemic, growing poverty, increased immigration from high-risk countries, and deterioration of tuberculosis control programs. In 1994, 24 261 cases of tuberculosis were reported in the United States and 1670 persons died of the disease. Worldwide, about 1.7 billion persons currently have tuberculosis, and the disease kills about 3 million persons per year. Infection with Mycobacterium tuberculosis is thus the leading cause of death from infectious disease, accounting for 6% of all deaths.

The increased number of cases of and deaths from tuberculosis in the United States is accompanied by another problem-multidrug-resistant strains of M. tuberculosis. Multidrug-resistant tuberculosis is defined by resistance to isoniazid and rifampin, the two best drugs. Resistance to these drugs leaves few treatment options with established effectiveness. So far, 60% of the strains of multidrug-resistant M. tuberculosis have been found in New York City, and these strains account for almost one fifth of all cases of tuberculosis reported in New York City. In 1991, the rate of resistance to isoniazid or rifampin was 14% in the United States and 33% in New York City; the rate of resistance to both isoniazid and rifampin was 3% in the United States and 19% in New York City. A more recent report showed that “strain W” in New York City accounted for nearly one fourth of all cases of multidrug-resistant tuberculosis occurring during a 43-month period that began on 1 January 1990. This strain is resistant to at least six agents. Most multidrug-resistant strains are nosocomially acquired, and most are seen in HIV-infected patients [3].

Previous reports emphasize the high mortality rate and low cure rate seen with multidrug-resistant tuberculosis. Park and colleagues examined the outcome of patients who received aggressive treatment. In this review, the authors looked at the clinical findings, laboratory results, and outcomes of 173 patients hospitalized at Bellevue Hospital in New York City from 1983 to 1994 with multidrug-resistant tuberculosis.

The mean age of infected patients was 40 years. Ninety-two percent were men, 80% were African-American or Hispanic, 21% were homeless, 52% were known to have HIV infection, and 25% had been born in another country. An acid-fast bacilli smear of the initial three sputum samples was positive in 94 of 171 patients (55%). In immunocompetent patients, the overall survival rate was 61% and the median duration of survival was greater than 120 months. In patients with AIDS, the median duration of survival was 6.8 months.

The 55% diagnostic yield seen with acid-fast bacilli smears (sensitivity) suggests that the diagnosis of tuberculosis is commonly delayed; this has important epidemiologic implications for multidrug-resistant tuberculosis in the hospital setting. The guidelines from the American Thoracic Society and the CDC, which advocate a four-drug regimen, would have led to inadequate initial treatment in 34% of these patients [4]. The overall prognosis of these patients was better than that previously reported in other patients. Other key points to emerge from this study are the importance of directly observed therapy, early detection as a prime factor in the outcome of therapy, and the possible disadvantage of clustering patients with AIDS in hospitals [2, 3].

Resistance to Streptococcus pneumoniae Is Now Common

Hofmann J, Cetron MS, Farley MM, Baughman WS, Facklam RR, Elliott JA, et al. The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta. N Engl J Med. 1995; 333:481-6.

If, in 1980, infectious disease specialists had tried to predict what would be the most problematic pathogen in 1990, they probably would have picked gram-negative rods. The surprise was that although many specialists predicted escalating antibiotic resistance among many organisms, few expected the problematic pathogens to be gram-positive cocci or fungi. These include Staphylococcus aureus, coagulase-negative Staphylococcus, Candida species, Enterococcus, and Streptococcus pneumoniae.

Streptococcus pneumoniae is a common cause of otitis media, sinusitis, meningitis, pneumonia, and bacteremia. Concern about the development of drug resistance has recently been growing, but in the United States, most reports of resistance have dealt with children in day care centers and the indiscriminate use of antibiotics. Hofmann and colleagues determined the susceptibility of Streptococcus pneumoniae in a population-based surveillance for invasive pneumococcal infections in Atlanta, Georgia.

In vitro sensitivity tests were done on Streptococcus pneumoniae isolates from 431 patients who had invasive disease during the first 10 months of 1994. Invasive disease was defined as positive isolates from usually sterile body sites.

The incidence of invasive infection during the study period was 30 cases per 100 000 persons. The rate of resistance to penicillin was 25%. Rates of resistance to other antimicrobial agents were the following: trimethoprim-sulfamethoxazole, 26%; erythromycin, 15%; cefotaxime, 9%; tetracycline, 8%; and imipenem, 6%.

Resistance of Streptococcus pneumoniae to drugs is a serious clinical problem in Atlanta. Further, the frequency of resistance has subsequently increased in Atlanta, and this changing pattern is now found in many metropolitan areas. A more recent report of 1527 isolates of Streptococcus pneumoniae from 30 medical centers showed that 24% of strains were relatively resistant to penicillin [5]. The annual burden of Streptococcus pneumoniae infections in the United States is 3000 cases of meningitis, 40 000 cases of bacteremia, 500 000 cases of pneumonia, and 7 million cases of otitis. Obviously, the potential effect of antibiotic resistance is huge.

Moreover, because many Streptococcus pneumoniae isolates that are resistant to penicillin are also resistant to many antibiotics, it is becoming increasingly difficult to recommend agents for empirical treatment of the infections listed in the preceding paragraph. The current recommendation for pneumococcal meningitis is vancomycin (which is active against all strains of Streptococcus pneumoniae but does not penetrate the blood-brain barrier well) plus cefotaxime or ceftriaxone (both of which are active against most strains and have well-established efficacy in pneumococcal meningitis). Implications for empirical treatment of pneumonia are unclear. Most important, recommendations for treatment of otitis and sinusitis-the illnesses in which antibiotics are most frequently used and abused-have become extremely difficult to make. The recommendations that are now almost universally accepted are reduction in the unnecessary use of antibiotics and broader use of pneumococcal vaccine [6]. The vaccine includes the serotypes that represent 89% of the isolates associated with resistance [7].

New Infections Continue To Emerge

Bennett D, Brown D. Ebola virus: poor countries may lack resources to prevent or minimize transmission [Editorial]. BMJ. 1995; 310:1344-5.

Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. 1996; 347:921-5.

The toll in deaths and disability from epidemics in the past decade has generally been caused by previously known pathogens (Table 2). However, new pathogens, such as those responsible for Ebola fever and “mad-cow disease,” are worrisome because their mortality rates are high and effective treatment is thus far unavailable.

In the spring of 1995, an outbreak of Ebola virus occurred in Kikwit, a city in western central Zaire. Health care workers were the first and eventually the major group to be infected. Epidemiologic studies suggested that the virus is spread by contact with body fluids, although the outbreak of Ebola virus in primates in a U.S. laboratory later suggested that respiratory spread may be possible. The incubation period for Ebola virus infection is about 7 to 14 days; this means that infected persons can travel before illness occurs, creating the potential for wide geographic spread. The control of Ebola virus currently focuses on epidemiologic techniques: surveillance, rapid response teams for outbreaks, careful handling of biological samples and infected bodies, and isolation of persons exposed to the virus.

Wealthier countries are also subject to new infectious diseases. Because of the epidemic of bovine spongiform encephalopathy among cows in England, surveillance of Creutzfeldt-Jakob disease was reinstituted in May 1990. These two illnesses are distinct transmissible spongiform encephalopathies that have an incubation period of years and are caused by infectious agents that appear to contain no nucleic acid and are extremely resistant to inactivation. About 150 000 cases of bovine spongiform encephalopathy have occurred in cattle since 1990, and 10 cases (of the 207 cases investigated) of Creutzfeldt-Jakob disease in humans have been identified that carried a new neuropathologic profile that may be connected to bovine spongiform encephalopathy. These 10 patients, 8 of whom have died, were all younger than 45 years of age; this characteristic is unusual for Creutzfeldt-Jakob disease. It has been hypothesized that the variant results from the recycling of cow and sheep products into animal feed, a practice that was discontinued in the United Kingdom in 1988. Although the outbreaks of both bovine spongiform encephalopathy and illnesses with the new type of Creutzfeldt-Jakob disease have remained confined to the United Kingdom, the relation between the two diseases remains controversial. The potential link is largely based on time (a 5- to 10-year incubation period), geographic location, and lack of an alternative explanation. The economic effect in the United Kingdom is enormous-the export of British beef and consumption of British cattle older than 30 months of age have both been banned [8].

HIV Infection and AIDS

The past year has been a success in terms of major advances in the management of HIV infection and the opportunistic diseases associated with it (Table 3). Perhaps for the first time, the outlook for persons infected with HIV appears less than bleak, although the spread of the epidemic goes on almost unabated.

HIV Replicates and Mutates Rapidly

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; 271:582-6.

Our previous understanding of the natural history of HIV infection was a belief that the virus remained latent for long periods in infected patients who appeared to be well. It was also suspected that some cofactor might be involved in the initiation of replication of the virus, leading to the depletion of CD4+ T cells and the development of illness after an average of 10 years from the time of HIV transmission.

Perelson and colleagues used a mathematical model to analyze data on HIV type 1 viral load that were collected from five infected but asymptomatic patients after they were given ritonavir, a protease inhibitor. The researchers estimated that infected cells had a median lifespan of 2.2 days (half-life, 1.6 days) and that the plasma virion had a median lifespan of 0.3 days (half-life, 0.24 days). The estimated production of HIV occurred at a rate of 10.3 × 10⁹ virions per day. The mean time needed for HIV generation (the time from release of a virion into the plasma until it infects another cell and causes release of a new generation of viral particles) is 2.6 days.

Perelson and colleagues describe the therapeutic consequences of their data. First, the effect of any anti-HIV agent should be measurable in decrement of viral load after a few days of treatment. Second, by using previous data on frequency of viral mutation, they estimate that many HIV mutations will occur, making monotherapy unlikely to succeed. Instead, they suggest, optimal therapy should completely inhibit HIV so that there is no opportunity for evolution of resistance that requires replication. This theory explains the strategy of using several drugs. Third, the virus may be most vulnerable shortly after it is introduced into the body, before it has established latency and developed drug resistance. The treatment tactic that takes advantage of this vulnerability is commonly referred to as “hit early and hit hard” [9].

RNA Replaces CD4+ Cells as the Superior Marker

Mellors JW, Kingsley LA, Rinaldo CR Jr, Todd JA, Hoo BS, Kokka RP, et al. Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion. Ann Intern Med. 1995; 122:573-9.

Until now, the most common clinical marker of progression of HIV disease was the level of circulating CD4+ T lymphocytes. Mellors and colleagues studied the relation between quantitative HIV RNA and the risk for AIDS or decline in CD4+ cell count after HIV seroconversion.

The Multicenter AIDS Cohort Study is a longitudinal study of homosexual men seen at 6-month intervals. Enrollment began in 1984. Plasma samples were stored, HIV serologic testing was done to determine the time of seroconversion, and CD4+ cell counts and other clinical and laboratory variables were measured every 6 months. Mellors and colleagues retrospectively analyzed stored plasma samples using a branched-chain DNA assay for quantitative measurement of HIV RNA levels; these levels were then correlated with clinical and laboratory observations.

Sixty-two persons participated, including 18 (29%) who developed AIDS, 21 (34%) who had a significantly decreased CD4+ cell count, and 23 (37%) who had a stable CD4+ cell count. The results showed that initial plasma HIV RNA levels are a strong predictor of the rate of progression to AIDS after HIV seroconversion and that this effect is independent of the CD4+ cell count. In a multivariable analysis of all laboratory values that were measured at the initial clinical visits and were associated with seroconversion, a plasma HIV RNA level of more than 10⁵ copies/mL was the most powerful predictor of progression to AIDS. Plasma HIV RNA levels also predict clinical response to antiviral agents [10]. Protease inhibitors, in combination with nucleoside analogues, decrease HIV RNA levels by about 100- to 1000-fold [11]. Studies of vertical transmission have shown that maternal RNA levels less than 20 000 copies/mL are associated with a markedly reduced chance of transmission to newborns [12]. Quantitative HIV virology is now well integrated into clinical practice and has become the major mechanism with which to monitor therapy [10].

Risk after Needlestick Is Stratified

Case-control study of HIV seroconversion in health-care workers after percutaneous exposure to HIV-infected blood-France, United Kingdom, and United States, January 1988-August 1994. MMWR Morb Mortal Wkly Rep. 1995; 44:929-33.

It has been estimated from previous surveillance studies that the risk for HIV transmission by needle stick injury from an HIV-infected source is about 0.3%. However, the factors influencing that risk were unknown.

This three-country case–control study compared various risks of 31 health care workers who were infected through needlestick injuries with the risks of 670 health care workers who received needlesticks but had no seroconversion. The investigators analyzed the outcomes of persons infected from 1990 through 1994, when administration of zidovudine was offered after a needlestick injury. The four risk factors that contributed most to transmission are given in Table 4. The use of zidovudine was associated with an adjusted odds ratio of infection of 0.21 (95% CI, 0.06 to 0.57), reflecting a fivefold reduction in rates of transmission.

On the basis of these results, the revised guidelines of the U.S. Public Health Service now recommend that health care workers exposed to HIV receive prophylaxis with zidovudine (200 mg three times daily) and lamivudine (150 mg twice daily) for 4 weeks. The guidelines recommend that indinavir (800 mg three times daily) should be added for persons with high-risk injuries and, because of concerns about drug resistance, for persons injured from a patient source who has received zidovudine and lamivudine.

Another Herpesvirus Disease: Kaposi Sarcoma

Moore PS, Chang Y. Detection of a herpesvirus-like DNA sequence in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med. 1995; 332:1181-5.

Kaposi sarcoma remains the most common neoplasm in patients with AIDS. Epidemiologic evidence (homosexual men are 20 times more vulnerable than are persons with hemophilia) has suggested that Kaposi sarcoma is associated with an infectious agent; moreover, the frequency of this neoplasm has sharply decreased, presumably because homosexual men have modified their behavior in response to the risk for HIV transmission.

In this laboratory study, Moore and Chang used a case–control design and a new method to detect short DNA sequences known as “representational difference analysis.” They studied DNA in tissue samples from case-patients: patients with Kaposi sarcoma lesions associated with HIV infection, homosexual men with Kaposi sarcoma lesions but not HIV infection, and persons with classic African-type Kaposi sarcoma. Control tissues included samples of uninvolved tissue from these patients and tissue from healthy volunteers. The samples were tested blindly by polymerase chain reaction (PCR) with specific primers to amplify herpesvirus-like DNA sequences.

The PCR product was found in 20 of 21 tissues from patients with Kaposi sarcoma and only 1 of 21 control samples. Representative PCR-product sequences showed more than 98% homology for the variable forms of Kaposi sarcoma, suggesting that all three types were caused by the same agent. This presumably represents a new human herpesvirus and a new oncogenic virus that is designated as either “Kaposi sarcoma herpes virus” (KSHV) or “human herpes virus 8” (HHV8) [13]. Subsequent studies have supported the role of HHV8 in Kaposi sarcoma, selected B-cell lymphomas, and diverse skin lesions [14-16].

Guidelines for Opportunistic Diseases Were Developed

USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: a summary. Ann Intern Med. 1996; 124:349-61.

Opportunistic infections decrease quality and duration of life for the estimated 700 000 persons living with HIV infection in the United States. In the late 1980s, efforts to decrease the incidence focused, with much success, on Pneumocystis carinii pneumonia and disseminated M. avium complex disease.

In 1994, the U.S. Public Health Service-mainly through the CDC, the National Institutes of Health, and the Infectious Diseases Society of America-developed recommendations for preventing opportunistic infection. Guidelines were graded according to the strength of each recommendation and the quality of the evidence that provided the basis of the recommendation. Prevention guidelines for major opportunistic infections are shown in Table 5.

Unfortunately, these guidelines have the limitations of all clinical guidelines: They quickly become outdated as new research findings are published. For example, prophylaxis for M. avium complex disease prolongs survival, and both clarithromycin and azithromycin have been proven to be superior to rifabutin for this prophylaxis. Consequently, many authorities would probably move prophylaxis for M. avium complex disease from a “consider” category to a “high priority” category and would advocate a macrolide agent. Nevertheless, these guidelines are a giant step forward in an era when standards of care are in great demand. The problem is the need for constant updating.

Resistance to Protease Inhibitors May Emerge

Condra JH, Schleif WA, Blahy OM, Gabryelski LJ, Graham DJ, Quintero JC, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature. 1995; 374:569-71.

Protease inhibitors (saquinavir, indinavir, and ritonavir) are widely viewed as the most exciting development in the 10 years of HIV therapy. The first-generation agents were nucleoside analogues (zidovudine, didanosine, zalcitabine, stavudine, and lamivudine) that had verified antiretroviral activity in vitro and clinical therapeutic benefit. In many instances, the effects of these drugs were time limited; this limitation was largely ascribed to the development of resistance, which was idiosyncratic to the particular drug. A major question is whether similar problems with resistance will develop with protease inhibitors.

In Condra and colleagues' study, patients treated with indinavir had viral studies at periodic intervals to determine susceptibility of HIV isolates to six protease inhibitors. Four patients were studied at variable frequencies. At 24 weeks of treatment, patient A showed a fourfold reduction in susceptibility to indinavir and increased resistance to two other protease inhibitors. Sequencing of DNA showed five to six amino acid substitutions. By week 40, the new viral variants showed numerous additional amino acid substitutions and increased resistance to all six protease inhibitors tested. Isolates from other patients showed distinctly different patterns with sequential samples and also showed cross-resistance.

Although the patient group was extremely small, this study provides the first evidence that exposure to some protease inhibitors can lead to the rapid emergence of drug-resistant variants in vivo and, more importantly, that this resistance may extend to other structurally diverse protease inhibitors.

The observations in this report are not universally accepted, and their biological meaning is not yet clear. This paper was selected for this Update to express the general concern about resistance to antiviral agents in the treatment of HIV infection and to call attention to the compelling need for rigorous attention to resistance in designing therapeutic strategies. Clearly, treatment with protease inhibitors includes three rules. First, patients should receive combination therapy, which usually includes nucleoside analogues. Second, patients must take all drugs at full doses. Third, once therapy with the drugs begins, it should not be stopped except for drug failure or toxicity.

When to begin this therapy remains a topic of great debate. Some favor early initiation, reasoning that a low viral load will result in fewer resistance problems and a higher likelihood of decreasing viral levels-perhaps to 0. Others favor using these drugs only after nucleoside analogue treatment has failed.

One other issue compounds the arguments. The cost of combination therapy runs about $12 000 a year. This seems expensive over the course of infection, but a cost-effectiveness analysis showed that “triple therapy” (zidovudine plus lamivudine plus indinavir) costs $10 000 to $18 000 per year of life preserved [17]. To place this figure in perspective, the cost-effectiveness of mammography in women older than 40 years of age is about $30 000 per year of life saved. The cost-effectiveness is $50 000 for hemodialysis and about $113 000 per year of life saved for a middle-aged man having coronary artery bypass grafting for three-vessel disease.

Number of AIDS Cases in the United States Exceeds One Half Million

First 500,000 AIDS cases-United States, 1995. MMWR Morb Mortal Wkly Rep. 1995; 44:849-53.

Rosenberg PS. Scope of the AIDS epidemic in United States. Science. 1995; 270:1372-5.

Karon JM, Rosenberg PS, McQuillan G, Khare M, Gwinn M, Petersen LR. Prevalence of HIV infection in the United States, 1984 to 1992. JAMA. 1996; 276:126-31.

The CDC report marks a numeric milestone in HIV-related disease in the United States. As of 31 October 1995, 501 310 persons with AIDS had been reported to the CDC since the epidemic began in 1981. Of those persons, 62% had died. Of the total, 10% were reported through 1987, 41% from 1988 through 1992, and 49% since 1992.

The proportion of cases among white persons decreased from 60% to 42% during those three periods, whereas the proportion increased from 25% to 38% for blacks and from 14% to 18% for Hispanics. The number of cases of AIDS associated with injection drug use increased from 17% to 27% during the three periods, and the rate of heterosexual transmission increased from 3% to 10%. In contrast, the rate of homosexual transmission decreased from 65% to 45% of all cases reported.

The incidence of AIDS seems to have reached a plateau in recent years, presumably as a result of both a decrease in the number of new infections and medical advances that have slowed the progression from asymptomatic infection to AIDS. The estimated prevalence from three data sources is that about 0.3% of U.S. residents (650 000 to 900 000) were living with HIV infection in 1992. The analysis by Rosenberg and colleagues provides estimates of prevalence by demographic characteristics, as summarized in Table 6. These data suggest that about 0.8% of young adult men are infected with HIV.

Primary Care Physicians Missed Common Signs of HIV Infection

Paauw DS, Wenrich MD, Curtis R, Carline JD, Ramsey PG. Ability of primary care physicians to recognize physical findings associated with HIV infection. JAMA. 1995; 274:1380-2.

Paauw and colleagues assessed the ability of primary care physicians to identify some of the physical findings of HIV infection. One hundred thirty-four general internists and family physicians were randomly selected after stratification by year of medical school graduation, specialty, and experience in caring for patients with HIV infection. The findings evaluated were Kaposi sarcoma, oral hairy leukoplakia, and diffuse lymphadenopathy; patients with these conditions were used for the evaluation.

Despite histories suggesting the physical abnormalities, only 23 of 89 physicians (25.8%) identified the purple nodule of Kaposi sarcoma, 22 of 97 (22.7%) recognized hairy leukoplakia, and 23 of 133 (17%) detected diffuse lymphadenopathy. Physicians with more experience in treating HIV-infected patients more frequently discovered hairy leukoplakia but not the other abnormalities. No differences were seen between internists and family physicians or among various graduation cohorts. These observations trigger concern about the current level of the expertise of primary care providers in recognizing common features of HIV infection.

A subsequent report [18] showed that physicians' experience with HIV had a significant effect on the survival of HIV-infected patients. The median survival of patients cared for by physicians with the greatest experience was 12 months longer than that of patients who were cared for by the least experienced [18]. The conclusions of this study may well be magnified in the era of protease inhibitors.

Dr. Roberts (Series Editor): York Health System, York, PA 17403.