Selection by AZT and Rapid Replacement in the Absence of Drugs of HIV Type 1 Resistant to Multiple Nucleoside Analogs

We studied the intrahost evolution and dynamics of a multidrug-resistant HIV-1, which contains an insertion of two amino acids (aa) and several aa changes within the reverse transcriptase (RT) gene. From an individual receiving intermittent therapy, sequences of 231 full-length molecular clones of HIV-1 RT were obtained from serum-derived viruses at 12 consecutive time points over a period of 6 years, 17 to 20 clones per time point. In the 3.5-year period prior to the first course of therapy, only wild-type (wt) viruses were found. As soon as 6 months after the start of zidovudine (AZT) monotherapy, all viruses contained an insertion of two aa between positions 68 and 69 of the RT and aa changes at positions 67 and 215, a combination conferring resistance to multiple nucleoside analogs. After termination of therapy, the insertion mutants were rapidly and completely replaced by the wt viruses. In turn, the insertion mutants replaced the wt viruses after initiation of therapy with 3TC, d4T, and saquinavir. After termination of triple therapy, the wt viruses completely replaced the mutants within 1 month, which is markedly faster than has been observed earlier for the replacement of AZT-resistant viruses. Fast replacements of the mutant virus populations after termination of therapy indicate gross competitive disadvantage of the insertion mutant in the absence of therapy, which we estimated by using several models. The insertion mutants attained high virus loads, demonstrating that virus load cannot be used as a direct measure of virus fitness

AIDS in the Netherlands, clinical and microbiological data in 36 cases

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Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

Additive or sequential nucleoside analogue therapy compared with continued zidovudine monotherapy in human immunodeficiency virus-infected patients with advanced disease does not prolong survival: an observational study

To study the effect of sequential or additive use of zalcitabine or didanosine on survival in 308 human immunodeficiency virus-infected patients with advanced disease treated with zidovudine, an observational study using time-dependent Cox proportional hazards models was done. Changing to sequential or additive therapy was based on deterioration of a patient's health status, a significant drop in CD4 cell count, or intolerance for zidovudine. The median CD4 cell count at baseline was 110 x 10(6)/L; 42% of patients had AIDS. The median count before a change in therapy was 50 x 10(6)/L. Additive or sequential treatment was associated with an increased risk for death (relative hazard, 1.59; 95% confidence interval [CI], 1.01-2.49; and 1.58; 95% CI, 1.10-2.37, respectively). Adjustment of the models for prognostic factors failed to substantially affect this observation. Possibly the lack of benefit in this study is because patients switched therapy at advanced stages, whereas the switch may be more effective in early diseas

Clinical features and risk factors of lactic acidosis following longterm antiretoviral therapy: 4 fatal cases

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