HIV/AIDS Research

Measuring a patient's viral load helps predict amount of time until HIV infection progresses to AIDS

The amount of time that it will take for patients infected with the human immunodeficiency virus (HIV) to develop AIDS can be predicted by the amount of viral RNA in their blood, according to a recent study that was supported in part by the Agency for Health Care Policy and Research (HS07782).

The investigators constructed a mathematical model to predict the time to symptomatic disease based on viral load measurements from longitudinal observations of untreated patients with asymptomatic HIV infection and CD4 cell counts greater than 500. For different viral loads, they calculated the time to progression to AIDS using a wide range of estimates for the time since seroconversion and the rate of change of viral load over time.

The investigators found that without antiretroviral treatment, asymptomatic HIV-infected patients with a viral load of 105 copies of viral RNA/ml serum are at risk of developing AIDS in less than 3 years, and patients with a viral load that is half a log higher (105.5) may develop AIDS in less than 1 year. In stark contrast, for patients with a viral load of 104.5, it may be at least 2 years or as many as 8 years before they develop AIDS; patients who have a viral load of 104 have 3 to 19 years before developing AIDS, according to the study.

Using viral load as a marker of disease status is important for guiding therapy during all stages of the disease, especially when the CD4 cell count, a marker of immune system deficiency, is maintained at levels close to normal (about 1,000). This is true even if the exact time of seroconversion (development of antibodies to HIV in the blood, the signal of infection) is unknown, points out Joseph Lau, M.D., of Tufts University School of Medicine. In patients with advanced stages of disease, CD4 cell counts may provide better information than viral load for long-term outcomes, but changes over time in viral load may be more useful in determining the efficacy of antiretroviral treatment, explains Dr. Lau.

For more information, see "Predictive value of viral load measurements in asymptomatic untreated HIV-1 infection: A mathematical model," by John P.A. Ioannidis, M.D., Joseph C. Cappelleri, Ph.D., M.P.H., Dr. Lau, and others, in AIDS 10(3), pp. 255-262, 1996.

Studies explore risk of opportunistic infections and risks and benefits of medications for HIV-infected patients

Patients infected with the human immunodeficiency virus (HIV) that causes AIDS are at risk for developing fungal and bacterial infections that take the "opportunity" provided by a patient's weakened immune systems to attack the body. For example, the incidence of bacterial pneumonia in patients with AIDS in San Francisco is 9.4 versus .07 per 1,000 person-years in non-HIV-infected persons of similar age. Also, oral and esophageal candidiasis, the most common opportunistic fungal infections in HIV-infected patients, have recently become resistant to previously effective fluconazole therapy. Finally, antiretroviral therapy to delay progression of HIV disease often causes toxicity leading to discontinuation of treatment, or as in the case of zidovudine, is only effective for 1 to 2 years. These issues are explored in the following four studies recently published by researchers supported in part by the Agency for Health Care Policy and Research (HS07809), and led by Richard D. Moore, M.D., M.H.Sc., of the Johns Hopkins University School of Medicine.

Gebo, K.A., Moore, R.D., Keruly, J.C., and Chaisson, R.E. (1996). "Risk factors for pneumococcal disease in human immuno-deficiency virus-infected patients." The Journal of Infectious Diseases 173, pp. 857-862.

From 5 to 20 percent of HIV-infected persons die from pneumonia. This study shows that HIV-infected patients who are black, at an advanced stage of HIV infection (CD4 cell counts of 200 or less), and/or have a past history of pneumonia are at increased risk of developing pneumonia. Zidovudine treatment and pneumococcal polysaccharide vaccine given when the patient's CD4 cell count is 200 or more CD4 cells/mm3 (the patient is still capable of mounting an antibody response to the vaccine) seem to decrease this risk. The researchers studied patients at an HIV clinic who had pneumonia between January 1990 and July 1994 and compared them with HIV-infected persons who were not treated for pneumonia. Results showed that patients who developed pneumonia were nearly four times more likely to be black than controls, over three times as likely to have less than 200 CD4 cells/mm3, three times more apt to have a history of pneumonia, and six times as likely to have an albumin level of less than 3 g/dL. Patients who developed pneumonia also were less likely to have used zidovudine and pneumonia vaccine when they had CD4 cell counts higher than 200.

Maenza, J., Keruly, J.C., Moore, R.D., and others (1996, January). "Risk factors for fluconazole-resistant candidiasis in human immunodeficiency virus-infected patients." The Journal of Infectious Diseases 173, pp. 219-225.

There have been increasing reports of HIV-infected patients developing oral or esophageal candidiasis that is resistant to therapy with fluconazole. This study shows that advanced immunosuppression, indicated by low CD4 cell count, and increased exposure to oral azole medications increase the risk for developing fluconazole resistance. The researchers conducted a case control study to identify risk factors for development of this resistance in 25 patients with fluconazole-resistant candidiasis, whom they compared with controls who had treatment-responsive candidiasis. After their first episode of candidiasis, patients who later developed fluconazole resistance had more treated episodes than did matched controls (3.1 vs. 1.8) lower median CD4 cell counts (11 vs. 77/mm3), and greater median durations of all antifungal therapy (419 vs. 118 days) and systemic azole therapy (272 vs. 14 days). These findings raise the question of whether oropharyngeal candidiasis should be treated with topical agents whenever possible, reserving systemic azoles for patients with esophageal candidiasis or invasive mycoses, conclude the researchers.

Moore, R.D., Fortgang, I., Keruly, J., and Chaisson, R.E. (1996, July). "Adverse events from drug therapy for human immuno-deficiency virus disease." American Journal of Medicine 101 (7) pp. 34-48.

Adverse reactions to antiretroviral drugs and drugs that prevent Pneumocystis carinii pneumonia (PCP) in patients infected with HIV are common, but serious reactions requiring hospitalization are rare. These adverse reactions increase progressively as CD4 cell count declines, and they vary according to the sex and race of the patient, according to these researchers. They calculated the number of adverse reactions from use of zidovudine, didanosine, zalcitabine, cotrimoxazole, and dapsone in 1,450 urban, HIV-infected patients whose CD4 cell counts were 500 cells/mm3 or less. Overall adverse reactions were 16.2 per 100 person-years (PY) for dapsone; 24.1 per 100 PY for didanosine; 26.3 per 100 PY for zidovudine; 26.3 per 100 PY for cotrimoxazole; and 37 per 100 PY for zalcitabine. The adverse reactions increased significantly with a decline in CD4 cell count from more than 200 to less than 100 cells/mm3 for all drugs but dapsone. Women were more likely than men to have a bad reaction from didanosine and from cotrimoxazole. White patients were nearly twice as likely as black patients to have an adverse reaction to cotrimoxazole. Only 6 percent of all adverse reactions required hospitalization, and there were no deaths.

Moore, R.D., Keruly, J.C., and Chaisson, R.E. (1996, May). "Duration of the survival benefit of zidovudine therapy in HIV infection." Archives of Internal Medicine 156, pp. 1073-1077.

The ability of zidovudine (ZDV) therapy to prolong survival in HIV-infected patients is limited to between 1 and 2 years in patients with CD4 cell counts of 500/mm3 or less, perhaps due to the emergence of ZDV-resistant HIV. Beyond 1 year of ZDV use, changing to an alternative therapy—such as didanosine, zalcitabine, stavudine, or combination therapy—may be appropriate, conclude the authors. They determined the duration of ZDV benefit in 393 patients who were receiving HIV care at a large urban clinic; 57 percent of the patients were injecting drug users. They compared the 235 patients who used ZDV with the 158 nonusers and found that the risk of dying was reduced by two-thirds when ZDV was used for less than a year. However, this hazard declined only 25 percent by the second year. These findings demonstrate an early, though limited, benefit of ZDV in an urban, predominantly black population with a relatively high proportion of women and injecting drug users. This study preceded current work on combination therapies and contributed to the evolving knowledge base on treatment options for HIV-infected patients.

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