Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients

Clinical Department bLaboratory of Antiviral Drug Monitoring, National Institute of Infectious Diseases Lazzaro Spallanzani, IRCCS, Rome, Italy.
AIDS (Impact Factor: 5.55). 08/2005; 19(10):1081-9. DOI: 10.1097/
Source: PubMed


To evaluate the effect of drug class-wide resistance (CWR) on survival in HIV-infected individuals who underwent genotypic resistance test after antiretroviral failure.
Observational, longitudinal cohort study.
HIV-infected individuals experiencing treatment failure were enrolled at first genotypic resistance test. End-points were death for any cause, AIDS-related death and AIDS-defining event/death. CWR was defined according to the International AIDS Society consensus. Survival analysis was performed with Cox's model.
Among 623 patients enrolled and followed for a median of 19 months (interquartile range, 12-29), Kaplan-Meier analyses for end-points at 48 months in patients with no CWR, one CWR, two CWR or three CWR were 8.9, 11.7, 13.4 and 27.1%, respectively, for death; 6.1, 9.9, 13.4 and 21.5%, respectively, for AIDS-related death; and 16.0, 17.7, 19.3 and 35.9%, respectively, for new AIDS event/death. In a multivariate Cox's model, higher HIV RNA level, previous AIDS and detection of three CWR (hazard ratio, 5.34; 95% confidence interval, 1.76-16.24) were all significantly associated with increased risk of death, while higher CD4 cell count and use of a new boosted protease inhibitor drug after identifying genotypic resistance were associated with reduced risk. Detection of three CWR was also significantly associated with higher risk of AIDS-related death and new AIDS event/death.
Even in the late era of highly effective antiretroviral treatments, detection of CWR, particularly if extended to all three drug classes is related to poorer clinical outcome and represents a risk-marker of disease progression and death.

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    • "However, not all studies have found a higher prevalence of K65R in subtype C, and it is possible that such discordance is related to the duration of sub-optimal therapy in patients inadvertently experiencing virological failure. All studies reporting a low frequency of K65R have monitored virologic failure, while those that found high frequencies of this mutation monitored therapeutic failure based on immunological or clinical parameters, which require several months of surveillance after virological failure and resistance are suspected [65-67]. "
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    ABSTRACT: Ninety percent of HIV-1-infected people worldwide harbour non-subtype B variants of HIV-1. Yet knowledge of resistance mutations in non-B HIV-1 and their clinical relevance is limited. Although a few reviews, editorials and perspectives have been published alluding to this lack of data among non-B subtypes, no systematic review has been performed to date. With this in mind, we conducted a systematic review (1996–2008) of all published studies performed on the basis of non-subtype B HIV-1 infections treated with antiretroviral drugs that reported genotype resistance tests. Using an established search string, 50 studies were deemed relevant for this review. These studies reported genotyping data from non-B HIV-1 infections that had been treated with either reverse transcriptase inhibitors or protease inhibitors. While most major resistance mutations in subtype B were also found in non-B subtypes, a few novel mutations in non-B subtypes were recognized. The main differences are reflected in the discoveries that: (i) the non-nucleoside reverse transcriptase inhibitor resistance mutation, V106M, has been seen in subtype C and CRF01_AE, but not in subtype B, (ii) the protease inhibitor mutations L89I/V have been reported in C, F and G subtypes, but not in B, (iii) a nelfinavir selected non-D30N containing pathway predominated in CRF01_AE and CRF02_AG, while the emergence of D30N is favoured in subtypes B and D, (iv) studies on thymidine analog-treated subtype C infections from South Africa, Botswana and Malawi have reported a higher frequency of the K65R resistance mutation than that typically seen with subtype B. Additionally, some substitutions that seem to impact non-B viruses differentially are: reverse transcriptase mutations G196E, A98G/S, and V75M; and protease mutations M89I/V and I93L. Polymorphisms that were common in non-B subtypes and that may contribute to resistance tended to persist or become more frequent after drug exposure. Some, but not all, are recognized as minor resistance mutations in B subtypes. These observed differences in resistance pathways may impact cross-resistance and the selection of second-line regimens with protease inhibitors. Attention to newer drug combinations, as well as baseline genotyping of non-B isolates, in well-designed longitudinal studies with long duration of follow up are needed.
    Full-text · Article · Jun 2009 · Journal of the International AIDS Society
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    • "Increasing number of HIV-infected patients harbor multi-resistant strains [Sabin et al., 2005]. Given that multi-resistance is associated with an increased morbidity [Zaccarelli et al., 2005], such patients are often hospitalized and may be source-patients in occupational exposures [Beltrami et al., 2003]. The most recent cases of post-exposure prophylaxis failure occurred after exposure to source-patients harboring resistant HIV strains [Hawkins et al., 2001; Beltrami et al., 2002]. "
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    ABSTRACT: We report the case of a health care worker who received a post-exposure prophylaxis including an investigational drug, maraviroc, after a needle stick percutaneous injury to an HIV-infected patient with late-stage disease and harboring a multi-drug resistant virus. Post-exposure prophylaxis including maraviroc was pursued for a total of 28 days, with a weekly clinical and biological evaluation. Post-exposure prophylaxis was well tolerated, with no increase in liver function tests. The health care worker remained HIV-negative after a 6-month follow-up.
    Preview · Article · Jan 2008 · Journal of Medical Virology
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    ABSTRACT: In the last years there has been a rapid development of probability models and statistical analysis for technological and medical survival data. The proportional hazard model formulated by Cox (1972) has rapidly become one of the most widely used methods for the analysis of clinical data, turning into a very powerful tool that has served to generalize the use of the analysis of survival This model is particulary useful examining treatment comparisons based on the times to some event while adjusting for the effects of concomitant variables and easily adapts to the incomplete data which are frequent in medical research. We work with censored data on the right, for which we used the statistical package S-Plus. In this paper we applied the Coxs proportional hazard model in a study of 1366 women infected with AIDS in Andalusia (Spain) between the years 1982 and 2001 focusing on the following variables: age, time of diagnosis, province of residence and level of transmission. The main result has been an increase in the survival of women with the introduction of the "Antiretroviral Therapy Very Active" in 1996, women diagnosed in the period 1993-1995 have an irrigation die 2.3 times greater than that diagnosed after 1996. As for age, women 35 years and older have a risk of death 1.8 times higher than in women under 30. The province with the largest survival is Grenada. We have not found any differences in the category of transmission. The data has been provided by the Andalusian Registry of AIDS.
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