INFECTIOUS DISEASE CHALLENGES/HIV AND THE GENERAL INTERNIST
From Johns Hopkins University School of Medicine’s 50th Annual Topics in Clinical Medicine
| EMERGING AND RE-EMERGING INFECTIOUS DISEASES IN THE 21st CENTURY —Anthony S. Fauci, MD, Director, National Institute of Allergy and Infectious Diseases, Washington, DC |
| Introduction: infectious diseases second leading cause of death worldwide; major cause of death from birth to 45 yr of age; underlying high mortality—staple matrix of familiar diseases, eg, malaria, diarrheal disease, tuberculosis, respiratory illness; overlaid by continuously emerging and re-emerging diseases; 3 categories—1) “truly emerging” new infections, eg, HIV/AIDS and severe acute respiratory syndrome (SARS); 2) re-emerging infections, eg, West Nile virus leaped from Africa to Queens, New York; 3) “deliberately emerging diseases or re-emerging diseases,” eg, case of anthrax attack; 75% zoonotic—pathogens jump species, from primary species to secondary species, ie, human, who can assume role of primary species (eg, HIV from monkey to human, avian flu from chickens and ducks); delicate balance between—ability of microbes to emerge and re-emerge based on capability to replicate and mutate; humanity’s intellect, will, and ability to execute public health measures, research, and advanced technologies; aspects of research—basic research on pathogens and host; capacity, ie, training; genomics; resulting in countermeasures, ie, diagnostics, therapeutics, and vaccines; advances in genomics—DNA of newly identified microbe can now be sequenced in ≈1 day |
| HIV infection: prototype of new disease; recognized in United States with little awareness epicenter in sub-Saharan Africa; today >60 million infected, >20 million dead, 40 million living with HIV infection; United States—cumulative AIDS diagnoses almost 1 million; 0.5 million deaths; ≈1 million infected (50% untested or untreated or both); 40,000 new infections added each year; early rate of >100,000 new infections per year reduced, but plateaued at unacceptably high level, remaining at ≈40,000 per year; as demography of epidemic shifted, number of people infected remained stable; development of antiretroviral therapy—demonstrates impact of investing substantial resources in attacking particular public health problem; more Food and Drug Administration (FDA)-approved antiviral drugs for HIV than for all other viral infections combined; developing world—≈4 million in sub-Saharan Africa in need of drugs; 8% coverage, up from 1% 1 yr ago; represents early success of evolving programs with international support; United States’ President’s Emergency Plan for AIDS Relief $5 billion, 5-yr plan designed to prevent 7 million infections, treat 2 million HIV-infected people, and care for 10 million people, including AIDS orphans; multifaceted approach to prevention—includes interruption of mother-to-child transmission, condom use, topical microbicides, drug-abuse treatment, and vaccination; vaccine development—in every other infectious disease, human immune system capable of producing recovery and protective response; no documented case of HIV infection in which virus cleared from body, demonstrating extent of challenge |
| Malaria: ≈2 million deaths annually, mostly in children; technologic advances—genetic sequencing of Plasmodium falciparum and main vector, Anopheles gambiae mosquito; opens new approaches to treatment and vaccine development; new vaccine—against P falciparum; efficacy 30% in first clinical episode and 58% in severe malaria; represents significant advance |
| Influenza: virus designated by 2 antigens, hemagglutinin (H) and neuraminidase (N), and number, eg, last season H3N2; each year small changes in virus (drift) prompt minor modifications in vaccine; periodic pandemics—occur after jump in species, when major changes in virus (shift) render most, if not all, humans naive to antigen; 40 million died after appearance of H1N1 antigen in 1918; other pandemics in 1957 (H2N2) and 1968 (H3N2); current threat—avian influenza circulating in Asia; from 2004 to 2005, 89 laboratory-confirmed cases and 52 deaths recorded; H5N1 virus as yet unable to efficiently spread from human to human (necessary for pandemic); vaccine development—in August, after this presentation, New York Times reported vaccine against H5N1 had proven effective in clinical trials and that, according to Dr. Fauci, vaccine could be used on emergency basis while testing continues; oseltamivir (Tamiflu)—only effective therapy for H5N1 virus infection; now being stockpiled |
| Severe acute respiratory syndrome: spread worldwide via departing visitors infected at Hong Kong with guest from region of China where SARS first emerged in November, 2002; since epidemic of 2003 (8000 cases and almost 800 deaths), infections limited to laboratory workers; historic consequence—new technologies enabled shortest time from identification of new virus (March, 2003) to clinical trial of vaccine (December 2004) |
| West Nile virus: re-emerging infection; restricted to Africa and Middle East until virus identified in Queens, New York, in 1999; each year, hot spots of infection move as virus spreads to areas of immunologic naivete; pattern of spread—from Queens to New Jersey and parts of Pennsylvania in 2000; reached Florida in 2001; moved to Middle West in 2002 and to Great Plains in 2003; brought by birds across Rocky Mountains to West; status of disease—now endemic, with ≈2400 cases in 2004; level of infection expected to vary over next several years; technologic advance—West Nile and yellow fever both flaviviruses; genes from West Nile inserted into attenuated yellow fever vaccine, making chimera of 2 viruses; cuts ≈3 yr from vaccine development process |
| Marburg hemorrhagic fever: outbreak under way in Angola; mortality rate 90%; becomes transmissible only when disease advanced and patient essentially moribund; spread to United States via air travel virtually ruled out |
| Anthrax: example of emerging and re-emerging infection introduced through bioterrorism, resulting in 18 confirmed cases and 5 deaths; involved two components, “bio” and “terror”; “rather meager on the ‘bio’ but very big time on the terror”; response turned out to be boon for public health—infusion of resources into basic research applicable not only to agents of bioterrorism, but to all emerging and re-emerging infections; advanced development—government providing incentives for drug companies to produce diagnostics, therapeutics, and vaccines by guaranteeing their purchase, eliminating financial risks; results—>3 million doses of smallpox vaccine; new therapies and vaccines under development; involves work on anthrax, Ebola, botulinum toxin, as well as influenza |
| Questions and answers: why steady rate of new HIV infections—shifting demography, from gay men and injection drug users to inner-city minorities, with increased heterosexual transmission; complacency among gay men; injection drug use and crack cocaine for sex; allocation of resources—requires balance of treatment and prevention; “cannot just abandon a few million people”; tuberculosis—genetic sequencing led to first vaccine trial in 60 yr; influenza vaccine shortage— vaccine enterprise fragile, requires incentives to get companies to make investments; as for next season, vaccine supply expected to approach level sought last year; anthrax vaccination—doses for 25 million being stockpiled; targets include hazard management teams and people exposed |
| DIAGNOSIS AND MANAGEMENT OF HIV INFECTION: WHAT IS THE ROLE OF THE GENERAL INTERNIST?— Joel E. Gallant, MD, Associate Professor of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore |
| Diagnosis of HIV infection: most important thing general internist can do; primary HIV infection—symptoms occur in ≤90% of patients, typically 2 to 4 wk after infection; acute retroviral syndrome identical to many other viral illnesses (other symptoms uncommon, eg, neurologic); consider diagnosis in patients suspected of having mononucleosis (age group at risk for HIV infection); early diagnosis important for preventing further transmission during highly infectious period of peak viremia (when patients unaware of infection continue engaging in high-risk activity); obtain resistance test—≈14% of patients infected with virus resistant to ≥1 drugs, 3% resistant to multiple drug classes; consider early therapy—benefits uncertain; refer patients to clinical trial; testing—HIV serology usually negative or indeterminate early in infection; critical to obtain RNA viral load test; newly infected patients usually have high viral loads; low viral load could be false-positive; negative viral load does not mean patient HIV-negative but excludes acute retroviral syndrome as cause of symptoms; voluntary testing—indicated in hospitalized adults in areas where seroprevalence >1%; need to move toward perception of test as routine; testing and counseling consume less time than many think; laboratory markers of HIV infection—anemia; leukopenia (especially lymphopenia); thrombocytopenia; elevated total serum protein |
| When to start therapy: aggressive approach originally adopted with view toward eradicating HIV; rationale for deferring therapy—emerged in ≈2000 based on experience; failure of eradication hypothesis; side effects, long-term toxicity, poor quality of life, complexity and difficulty of adherence; lack of benefit in early cohort studies; latest Department of Health and Human Services (DHHS) guidelines—treat patients with AIDS or severe symptoms and CD4 count <200 cells/mm3 ; consider or offer therapy at CD4 count <350 cells/mm3 ; consider if viral load >100,000 cells/mm3 ; why more aggressive approach may return—in contrast to earlier regimens, current therapy stronger, involves 2 pills once daily, no food restrictions, and no known long-term toxicity; next year, 1-pill daily regimen expected to be introduced, decreasing challenge to adherence; cohort studies suggest treatment of patients with CD4 counts >350 cells/mm3 beneficial; prolonging HIV exposure may increase risk for dementia and non-Hodgkin’s lymphoma; starting early may maintain options for CD4-guided intermittent therapy (huge cost savings in developing countries would provide therapy to more people) |
| Antiretroviral therapy today: how to prescribe antiretroviral therapy beyond scope of this presentation; many drugs available, with 0 to 4 new drugs introduced each year; recommended in new guidelines—1 preferred protease inhibitor-based regimen; 1 preferred nonnucleoside-based regimen; many alternative regimens available; once-daily therapy provides convenience without sacrificing potency; grounds for rising expectations—data from >4000 patients in 5 cohorts in Europe and Canada demonstrate steady decrease in virologic failure and improvement in CD4 cell response; failure today more commonly due to nonadherence to therapy and loss to follow-up than virologic failure on medication; treatment failure—response to antiretroviral therapy not always ideal (ie, long-term suppression of viral load to below limits of detection); failures involve growing resistance to point where viral load cannot be suppressed by existing drugs; predictors of failure—primarily nonadherence; previous antiretroviral therapy; higher viral loads; lower CD4 counts; specific regimen used; physician inexperience |
| Targets for antiretroviral therapy: reverse transcriptase inhibitors and protease inhibitors aimed at original targets; entry inhibitors—first drug approved by FDA, enfuvirtide (T-20) [Fuzeon] inhibits final stage of viral entry, ie, fusion of virus with CD4 cell membrane; integrase inhibitors—inhibit final integration of reverse transcribed viral DNA into host DNA; now in clinical trials; maturation inhibitors—inhibit latest stages of viral maturation and assembly; other targets—every step of viral entry provides target for drug development, eg, attachment of gp120 on viral surface to CD4 receptor; CD4 attachment-inhibitors under development; viral attachment induces changes in gp120 that permit binding to CD4 coreceptors (CCR5 or CXCR4; both targets for drug development); coreceptor tropism—as HIV disease progresses, virus tends to shift from R5-tropic (binding to CCR5) to dual tropic or X4-tropic (binding to CXCR4 coreceptor), associated with more rapid disease progression; cause for concern—development of CCR5 inhibitors may lead to selection for more virulent X4-tropic virus; starting therapy earlier may impede emergence of X4-tropic virus, decreasing risk of harm when CCR5-inhibitors introduced |
| Deciding when and how to use new agents: “hardest thing we do”; effective therapy requires combination of drugs; too soon—new drug begun when not required by low CD4 cell count; combined with inactive or partially active drugs, allowing resistance to develop without availability of backup drug; too late—postponing introducing new drug until resistance to other drugs grows to point where combination therapy impossible; just right—new drug combined with other active new agents, or use deferred until other new agents available |
| Modify therapy early in course of failure: previous delays allowed numerous hard-to-treat mutations; in “experienced patients,” suppress viral load if possible; if not suppressible, continue therapy without accumulating resistance; use new agents only in combination other active agents |
| Include HIV expert in patient care: National Institutes of Health (NIH) recommends all patients be seen by expert; study found that compared with generalists (with 4 patients on average), HIV experts (average of 94 patients) decreased overall cost and hospital time in patients with more advanced disease; who qualifies as HIV expert—not necessarily infectious disease specialist; determined by experience (number of patients) and level of continuing medical education; models for expert care—HIV expert primary care physician; comanagement with primary care physician; periodic consultation with HIV expert, followed by communication with primary care physician |
| Physician resources: range of useful resources available at www.hopkins-aids.edu |
| Questions and answers: differing CD4 response in patients with undetectable viral loads—cause unknown; factors include patient age and baseline CD4 count set-point; if viral load suppressed, failure to mount good CD4 response not considered treatment failure and not reason to alter therapy; rapid HIV tests—speaker endorses both oral and finger-stick rapid tests; test of viral load required to diagnose acute infection (rapid tests often negative) |
Educational Objectives
| The goal of this program is to educate internists about infectious disease challenges and the role of the general internist in managing HIV infection. After hearing and assimilating this program, the clinician will be better able to: |
 | 1. Identify major emerging and re-emerging infections and the challenge they pose to public health worldwide. |
| 2. Explain recent advances in epidemiology, diagnostics, therapeutics, and vaccine development in the field of infectious disease. |
| 3. Diagnose HIV infection, especially primary HIV infection. |
| 4. Adopt the current approach to managing patients infected with HIV. |
| 5. Ensure that an HIV expert is involved in the management of patients with HIV infection. |
Discussed on This Program
Enfuvirtide (T-20) [Fuzeon] Oseltamivir phosphate [Tamiflu]
Suggested Reading
Aberg JA et al: Primary care guidelines for the management o.persons infected with human immunodeficiency virus: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 39:609, 2004; Blankson JN et al: Early treatment of HIV. Hopkins HIV Rep 16:14, 2004; Fauci AS et al: Emerging infectious diseases: a 10-year perspective from the National Institute of Allergy and Infectious Diseases. Emerg Infect Dis 11:519, 2005; Fauci AS: Emerging infectious diseases: a clear and present danger to humanity. JAMA 292:1887, 2004; Fauci AS: Race against time. Nature 435:423, 2005; Fauci AS: The global challenge of infectious diseases: the evolving role of the National Institutes of Health in basic and clinical research. Nat Immunol 6:743, 2005; Gallant JE: Approach to the Treatment-experienced Patient. Curr HIV/AIDS Rep 2:83, 2005; Gallant JE: Editorial comment: strategies for success--a return to "hit early"? AIDS Read 14:662, 2004; Gallant JE: Protease-inhibitor boosting in the treatment-experienced patient. AIDS Rev 6:226, 2004; Review. Gallant JE: The choice of the nucleoside backbone in initial therapy. Hopkins HIV Rep 16:1, 2004; Hirschberg R et al: Biomedical research--an integral component of national security. N Engl J Med 350:2119, 2004; Kalkut G: Antiretroviral therapy: an update for the non-AIDS specialist. Curr Opin Oncol 17:479, 2005; Landon BE et al: Physician specialization and antiretroviral therapy for HIV. J Gen Intern Med 18:233, 2003; Landon BE et al: Physician specialization and the quality of care for human immunodeficiency virus infection. Arch Intern Med 165:1133, 2005; Moyle GJ et al: Epidemiology and predictive factors for chemokine receptor use in HIV-1 infection. J Infect Dis 191:866, 2005; Nettles RE et al: Intermittent HIV-1 viremia (Blips) and drug resistance in patients receiving HAART. JAMA 293:817, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed: Dr. Gallant— Abbot Laboratories (honoraria); Boehringer Ingelheim (grant/research support); Bristol-Myers Squibb (grant/research support; consultant); Gilead Sciences (grant/research support; consultant; honoraria); Glaxo SmithKline (grant/research support; consultant; honoraria): Pfizer (grant/research support): Roche Pharmaceuticals (grant/research support; honoraria): Vertex (consultant); Tanox (grant/research support; consultant); Tribotec-Virco (grant/research support; consultant); ViraLogic (consultant; honoraria)
Drs. Fauci and Gallant were recorded at the 50th Annual Topics In Clinical Medicine, sponsored by Johns Hopkins University School of Medicine in Baltimore, May 2-6, 2005. The Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation in the production of this program.
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