Natural History, Epidemiolgy & Prevention
Research progress in this area includes:
Epidemiologic research has shown the demographics of HIV infection and AIDS in the United States changing from an illness primarily affecting homosexual and bisexual men to the current epidemic, with increasing rates of infection in heterosexual men and women, adolescents, minorities, and drug users.
The NIH conducts studies to examine the transmission of HIV and the progression of HIV-related disease, including opportunistic infections (OIs); malignancies; neurological, neurobehavioral, and oral manifestations; and other sequelae.
Such studies examine the effects of viral factors, host factors, and other factors on the risk of infection and disease progression.
Cohorts of HIV-infected individuals and HIV-uninfected individuals at risk of infection are followed in clinical epidemiology studies at domestic and international sites.
Major ongoing studies include:
NIAID supports the National AIDS Specimen Repository. The repository contains over one million biological specimens linked to a huge data base from fully characterized and longitudinally followed cohorts. These biomedical samples are available to the scientific community, in collaboration with study investigators. Similarly, the NCI supports a repository of specimens from subjects enrolled in cross-sectional and prospective studies, and the NHLBI supports a serum and cell repository of more than one million specimens from volunteer blood donors and recipients of blood components or plasma derivatives. The NIMH supports the National Neurological Research Specimen Bank, which collects and distributes central nervous system (CNS) specimens from HIV-infected donors and represents a valuable resource for basic science investigations.
International epidemiology studies conducted or supported by the NIH contribute significantly to the understanding of HIV transmission, progression of HIV-related disease, risk factors associated with HIV infection and AIDS, and biomedical preventive intervention strategies. NIAID has established the HIV Efficacy Trials Network (HIVNET) in preparation for vaccine and other prevention trials of biomedical interventions. These trials have already begun to evaluate mass STD treatment, microbicides, and perinatal interventions with antiretrovirals and immunotherapy, as well as behavioral approaches linked to biomedical interventions. The NIH-sponsored international collaborative epidemiology research activities such as the NIAID HIVNET and numerous studies supported by the NCI, NIDR, and FIC training programs, foster the development of research skills and infrastructure in countries where HIV infection and AIDS are epidemic, in order to facilitate biomedical and behavioral intervention trials as well as future international HIV vaccine efficacy trials.
Other studies are beginning to generate data on the transmissibility of non-B HIV clades and the reduction of HIV transmission through prevention and treatment of coexisting sexually transmitted infections as a means of primary HIV prevention. Another area of primary prevention research is focusing on reduction of perinatal transmission in the United States and worldwide, with particular emphasis on methods appropriate to the developing world.
The NIH investment in establishing and maintaining these domestic and international epidemiologic cohorts provides opportunities for epidemiologic and basic researchers to study unique populations, cooperatively pursue fundamental research on critical aspects of HIV transmission and disease, and understand in a population-based context the meaning of phenomena described by intensive lab-based studies. Population-based cohorts of high-risk HIV-uninfected persons remain critical to the elucidation of the natural history of primary HIV infection. Natural history and epidemiology research requires that special efforts be made to link the overall NIH research strategy with all facets of the international health research community through the OAR and FIC.
The DNA sequences discovered recently in Kaposi's sarcoma (KS) lesions appear to represent a new gamma-herpesvirus, provisionally termed human herpes virus type 8 (HHV8). This may represent the long-sought KS virus that, like Epstein-Barr virus, also may be involved in the etiology of some non-Hodgkin's lymphomas. A thorough understanding of the epidemiology and natural history of HHV8 is needed urgently. It is expected that the number of these malignancies will continue to increase as the life expectancy of HIV-infected patients is prolonged by administration of antiviral therapies and prophylaxis for HIV-related OIs.
A striking phenomenon has been the increase in tuberculosis (TB) and multidrug-resistant TB related to HIV infection, both globally and in certain populations in the United States. In response to the increasing incidence of TB, programs have been established to focus on the spread of TB among IDUs. Research efforts focus on the incidence and progression of TB in HIV seronegative and seropositive active drug users and development of improved screening and adherence strategies in order to reduce infectivity and transmission.
Additional attention needs to be devoted to study of the possible impact of OIs, such as TB, on influencing the natural history of HIV disease, including the possible influences of such infections on HIV concentration in body fluids and tissues. Ultimately this information could be useful in identifying future opportunities to prevent disease progression, and perhaps HIV transmission as well.
While many of the clinical manifestations of HIV infection in women are identical to those that occur in men, women also experience some that are unique and more prevalent than in men, such as vaginal and esophageal candidiasis, and chronic herpes simplex infections. The Women's Interagency HIV Study (WIHS), a major study conducted in collaboration with other PHS agencies, is identifying the nature and rate of HIV disease progression in women, characterizing clinical manifestations of HIV important to women, assessing the effects of therapeutic regimens, and identifying sociocultural and health care access factors that affect disease outcomes in women. An important concern is the impact of HIV on cervical cancer. Case reports suggest that HIV-associated cases progress more rapidly and are refractory to therapy. The NCI Surveillance, Epidemiology, and End Result (SEER) program has established a Special Surveillance Study to define more closely the incidence and spectrum of the histopathology of cervical cancer in HIV-infected women. The Multistate AIDS Cancer Match Registry is a project aimed at enhancing knowledge about HIV-associated cancer. Coinfection with human papillomavirus (HPV) is common in HIV-infected women. HPV and HIV have been shown to act synergistically to increase expression of individual viral genes. The enhanced expression of viral proteins results in increased viral replication, abrogates host tumor suppressor functions, and further exacerbates cellular immunodeficiency.
The NIH continues to study the progression of HIV-related disease in infants and pregnant women, including the timing, mechanisms, and risk factors of maternal-fetal transmission. The development of improved diagnostic assays for the early detection of HIV infection among infants, as well as markers predicting rapid versus slower disease progression, form an important part of this effort. In addition, quantitative assessment of viral concentration in body fluids and tissues, and its role as a determinant of vertical transmission and disease outcome, is ongoing.
In the United States, the NIH is funding a large epidemiologic study evaluating factors associated with risk of perinatal transmission, as well as factors associated with maternal and infant disease progression. This study, the Women and Infants Transmission Study (WITS), collectively funded by NIAID, NICHD, and NIDA, includes extensive laboratory studies as well as a specimen repository. Another pediatric epidemiologic study assessing cardiac and pulmonary complications among HIV-infected children (P2C2) is funded by NHLBI. Perinatal prevention trials in the United States are done within the Pediatric AIDS Clinical Trial Group with funding from NIAID and NICHD.
Internationally, a wide variety of perinatal HIV prevention transmission studies are under way. These include antiretroviral and immunotherapy trials in Africa, the Caribbean, and Thailand that are being funded by NIAID and NICHD. In addition, NICHD, NIAID, and FIC are collaborating on several studies in Africa to determine whether micronutrient supplementation can reduce mother-to-child transmission or ameliorate disease progression in HIV-infected children. Likewise, NCI, NIAID, and FIC are collaborating on studies in Africa to assess whether vaginal and neonatal cleansing with microbicides can reduce the risk of perinatal HIV transmission and to clarify the role of breastfeeding in HIV transmission.
Recent evidence suggests that co-infection with other viruses may result in increased morbidity. For example, data from P2C2 suggest that HIV-infected pregnant women may be at greater risk for delivering infants with congenital cytomegalovirus (CMV) infection, and that these infected children are more vulnerable to CMV morbidity in the first years of life. Data from WITS indicate that, among drug-using women, women who are co-infected with hepatitis C and have the highest RNA plasma hepatitis C levels are at the highest risk of transmitting HIV to their infants.
Subsets of NIAID cohorts, both adult and pediatric, are being characterized in terms of the virologic and immunologic parameters of rapid and slow progression. New data have shown that the amount of HIV circulating in the bloodstream is predictive of the rapidity of disease progression. In particular, the NIAID is investigating individuals who (1) do not become infected despite repeated exposure to HIV; (2) appear to show clearing of the virus after initial documented infection; (3) manifest infection without immunologic progression (long-term nonprogressors); and (4) maintain stable clinical state even with prolonged immunosuppression (long-term survivors). Special focus is being placed on host genetics and possible states of "resistance" to HIV infection and on characteristics of the viral strain. Information from these cohorts will be crucial in designing and evaluating new therapeutic approaches and vaccines. New reverse transcriptase polymerase chain reaction (PCR) technology has made quantification of HIV in plasma or serum highly reproducible, sensitive, and predictive of AIDS. This technology likely will facilitate the elucidation of the in vivo natural history of HIV infection and also sexual and mother-to-child transmission, particularly if the technology can be adapted to the analysis of genital and other body fluids.
For more information on Natural History, Epidemiology, and Prevention HIV/AIDS-related research at the NIH, contact:
Robert Eisinger, Ph.D.
Office of AIDS Research, NIH
Building 31, Room 4B62
Bethesda, MD 20892
(301) 402-8655 TELEPHONE
(301) 402-8638 FAX
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