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Researchers examine the benefits of potent antiretroviral therapy and treatment compliance among patients with HIV

Highly active antiretroviral therapy (HAART), in use since late 1995, clearly slows progression of infection with the human immunodeficiency virus (HIV) to AIDS. It does this by reducing HIV viral load in the blood and partially restoring immune competence (increasing the number of infection fighting CD4 cells in the immune system).

Although most people adhere to the HAART regimen during the first month of treatment, adherence begins to wane after that, according to a study supported in part by the Agency for Healthcare Research and Quality (HS10399). Other researchers participating in the Women's agency HIV Study (WIHS) demonstrated immediate negative effects among women who discontinued antiretroviral therapy. A second WIHS study found that HAART reduced progression of human papillomavirus (HPV) disease, which has been linked to cervical cancer, among HIV-infected women.

The WIHS is a multicenter longitudinal study involving 2,059 HIV-infected and at-risk women enrolled at six clinical sites in 1994 and 1995. It was cosponsored by the Agency for Healthcare Research and Quality, the National Institutes of Health, and the Centers for Disease Control and Prevention. The three studies are described here.

Gross, R., Bilker, W.B., Friedman, H.M., and Strom, B.L. (2001). "Effect of adherence to newly initiated antiretroviral therapy on plasma viral load." AIDS 15(16), pp. 2109-2117.

This study found that adherence to a newly prescribed antiretroviral drug, a single protease inhibitor (nelfinavir), determined whether or not levels of HIV in an individual's blood were suppressed to undetectable levels (less than 50 copies of HIV virus per ml), and that, unfortunately, adherence began to wane after the first month of therapy. The researchers observed adherence to nelfinavir (750 mg three times a day or 1,250 mg two times a day) by 41 HIV-infected patients with viral loads greater than 10,000 copies per ml. The subjects, who were followed for 4 months, had not taken a protease inhibitor previously and were referred to a clinical research center from Philadelphia HIV clinics during 1998 and 1999.

Overall, 61 percent of patients achieved undetectable viral loads. Those who achieved undetectable levels of HIV during the initial 4 months of nelfinavir therapy had greater adherence to the medication regimen (took a median of 93 vs. 70 percent of prescribed doses) than those who still had detectable levels of the virus. Similarly, only 4 percent of those in the "undetectable group" had a 7-day pill-taking gap, a so-called "drug holiday," compared with 44 percent of those in the detectable group, some of whom had multiple week-long "drug holidays." Patients who followed the medication regimen also had increased CD4 cell counts. Thus, viral suppression went hand-in-hand with CD4 cell count increases, although the impact of adherence on change in CD4 cell count was less strong.

Grant L.A., Silverberg, M.J., Palacio, H., and others. (2001). "Discontinuation of potent antiretroviral therapy: Predictive value of and impact on CD4 cell counts and HIV RNA levels." AIDS 15(16), pp. 2101-2108.

The need for antiretroviral therapy (ART) may be lifelong among HIV-infected people. However, due to developing drug resistance, toxicities, and side effects, they may not be able to stay on the same drug regimen indefinitely.

These researchers investigated trends related to the discontinuation of potent ART over a 3-year period (October 1996 to September 1999) among 1,058 women participating in the WIHS, who began potent ART before September 1999. In all, 21 percent of women discontinued all ART at some time by September 1999; 27 percent were always on therapy, but downshifted to mono- or combination therapy; and 52 percent continued to take potent ART once they started it.

Compared with women who continued on potent ART, women who discontinued all ART experienced large declines in CD4 cell counts and were over three times more likely to experience HIV RNA increases. During the four most recent study periods, median CD4 cell counts of those continuing to use potent ART, downshifting to non-potent ART, or discontinuing all ART were 352, 292, and 320, respectively. Similarly, during the three most recent study periods, the proportion of potent ART users with HIV RNA less than 400 copies/ml (undetectable levels) who continued potent ART, downshifted to non-potent ART, or discontinued all ART was 45, 28, and 20 percent, respectively.

Individuals with high HIV RNA levels were more likely to discontinue ART. Side-effects were the most common reason for discontinuation, and more than one-third of those discontinuing ART reported side-effects. CD4 cell count declines were larger among those who did not cite side-effects as the reason for discontinuation of ART.

Minkoff, H., Ahdieh, L., Massad, L.S., and others. (2001). "The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women." AIDS 15(16), pp. 2157-2164.

From 20 to 40 percent of HIV-infected individuals are likely to be diagnosed with cancer. Cervical cancer, the end stage of human papillomavirus (HPV)-associated cervical lesions, has been linked to HIV load and immune status. This study found that HAART altered the course of HPV disease in HIV-infected women by reducing HPV disease progression and increasing regression.

The investigators used Pap smears and cervicovaginal lavage for HPV DNA testing every 6 months of HIV-infected women participating in the WIHS in five cities. Pap smear findings from each woman's consecutive visits were defined as a pair. The investigators determined the proportion of all pairs that exhibited either regression or progression according to HAART exposure (two or more protease inhibitors).

Overall, women on HAART were 1.4 times more likely to experience regression, while those not on HAART were more likely to show HPV disease progression. These results are particularly striking, since women in both groups were comparably at risk in terms of the presence of lesions. Reduction of HIV load and restoration of host immunity via HAART might retard the progression of these cancers. On the other hand, HAART could have a direct antiviral effect on HPV, suggest the researchers.

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