Scandinavian Journal of Infectious Diseases

ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19

Trend towards Decreased Survival in Patients Infected with HIV Resistant to Zidovudine Peter C. Gøtzsche, Claus Nielsen, Jan Gerstoft, Carsten M. Nielsen & Bent F. Vestergaard To cite this article: Peter C. Gøtzsche, Claus Nielsen, Jan Gerstoft, Carsten M. Nielsen & Bent F. Vestergaard (1992) Trend towards Decreased Survival in Patients Infected with HIV Resistant to Zidovudine, Scandinavian Journal of Infectious Diseases, 24:5, 563-565, DOI: 10.3109/00365549209054641 To link to this article: http://dx.doi.org/10.3109/00365549209054641

Published online: 08 Jul 2009.

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Date: 30 March 2016, At: 03:46

Scand J Infect Dis 24: 563-565, 1992

Trend towards Decreased Survival in Patients Infected with HIV Resistant to Zidovudine PETER C . GQ)TZSCHE’, CLAUS NIELSEN2, JAN GERSTOFP, C A R S T E N M. NIELSEN2 a n d B E N T F. V E S T E R G A A R D *

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From the Departments of ‘Infectious Diseases, Rigshospitalet, and zVirology, Statens Seruminstirut, Copenhagen. Denmark

The survival of 35 patients with AIDS or advanced HIV infection on treatment with zidovudine was related to the viral sensitivity to the drug and to the CD4+ cell count. 14 patients died, the survivors were followed up for an average of 804 days. In a univariate Cox model, survival was strongly related to log IC, (p = 0.0003) and to the CD4+ count 0,= 0.0002). In a bivariate model, log IC, and the CD4+ count contributed to the prediction of survival (p = 0.12 and 0.06, respectively). Large studies of combination or alternation therapy with several anti-HIV drugs should be given high priority. P. C . GZtzsche; MD, MSc, Department of Infectious Diseases, Rigshospitalet, Tagensvej 20,

DK-2200 Copenhagen N , Denmark

INTRODUCTION The short-term clinical effect of zidovudine in HIV infection is well documented (1,2). However, viral resistance seems to occur in many patients after 6-12 months of treatment (3,4). Since development of drug resistance could b e an important contributory cause t o the disappointing long-term results with zidovudine ( 5 ) ,we studied t h e survival in patients with A I D S or advanced HIV infection in relation t o CD4+ cell count and viral resistance.

METHODS 35 patients, 10 with AIDS, 18 with symptomatic HIV infection, and 7 with asymptomatic infection but a low CD4+ cell count were selected. All but one were males and all participated in a randomized, double-blind dose-response study of zidovudine (6). 13 were treated with 400 mg, 9 with 800 mg, and 13 with 1200 mg daily. The mean age was 43 years (SD 9 years). After a mean of 7 months on zidovudine (range 5-10 months), viral sensitivity was measured with a biological assay based on production of HIV antigen in cultures of CD4+ lymphocytes infected with cell free virus (4). We used log ICo, for the sensitivity, since this parameter lead to less residual variation than log ICc,,or the arithmetric values when development of resistance was predicted from number of months on zidovudine in an earlier study (4). For convenience, sensitivity values were multiplied by 100 before taking the logarithm. Four patients (all of whom died during the follow-up period) were highly resistant to zidovudine (IC, > 10 pM);for those, the truncated value of 10 pM was used for IC,,(,, Survival status as of July 1 , 1991 was obtained from the Danish Population Register for all patients. The last year of the study the patients were treated openly with zidovudine, since the dose-response study was terminated on July 1, 1990. Survival from the date of the sensitivity assessment was related to log the simultaneously measured CD4+ count, and to dose using Cox’s proportional hazards model (BMDP statistical software).

RESULTS Immune status and viral sensitivity is shown in Table I. 14 patients (40%) died during the follow-up period after a n average of 439 days (median 361, range 77-952). The survivors were followed for a n average of 804 days (median 839, range 560-951).

564 P. C. G@tzscheet al.

Scand J Infect Dis 24

Table I. Immune status and viral sensitivity to zidovudine (n = 35)

CD4+ cells ( x 106/1)

G,(W)

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Log UCw

X

lo2)4$(

Mean

SD

Median

Range

154 2.9 1.9

121 3.5 0.8

160 0.8 1.9

W18 0.08-10+ 0.9&3+

In univariate models, survival was strongly related to log IC, (p = 0.0003) and to the CD4+ count (p = 0.0002). When a backward elimination procedure was used (p = 0.15 for exclusion), dose was removed (p = 0.73), leaving contributions from log IC, and from the CD4+ count (p = 0.12 and 0.06, respectively; the coefficients (SE) were 0.80 (0.55) and -0.007 (0.004)). DISCUSSION As expected, the CD4+ count was a strong predictor of survival. It is noteworthy, however, that after a short course of therapy with zidovudine, viral resistance seemed to contribute independently to the prognosis. In the Cox analyses, the correlation between the estimated regression coefficients for the 2 variables was 0.55, which indicates that those who died tended to have both a low CD4+ count and a high level of resistance. The study is hampered by its small sample size. It could be argued, however, that 1-sided p values are more relevant than 2-sided ones, since it would be highly implausible to imagine improved survival with increased resistance or with decreased CD4+ counts. The 1-sided p values would be 0.06 and 0.03, respectively. Within the dose interval 400-1200 mg daily, no dose-response relationship seems to exist for the effect of zidovudine on survival (5,6,8) which is in agreement with the finding that dose has no influence on the rate of development of resistance (4,7). The cause-effect relationship between the CD4+ count and resistance could be bilateral. A low CD4+ count is associated with a high viral replication rate, increasing the likelihood of development of resistant strains (4,7), which in return might accelerate the decrease in the CD4+ count. The present study suggests but has not definitely proved the putative role of zidovudine resistance in explaining the long-term failure of treatment. The high correlation between resistance and the CD4+ count implies that rather large studies are needed to give the final answer to the question. Such studies should be given high priority, especially if designed as combination or alternation therapy with several anti-HIV drugs.

ACKNOWLEDGEMENTS This work was supported by the Danish Medical Research Council and the Danish Insurance Association.

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Trend towards decreased survival in patients infected with HIV resistant to zidovudine.

The survival of 35 patients with AIDS or advanced HIV infection on treatment with zidovudine was related to the viral sensitivity to the drug and to t...
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