HIV type 1 BF recombinant strains exhibit different pol gene mosaic patterns: descriptive analysis from 284 patients under treatment failure

Different complex structures of the pol gene have been identified in 284 HIV-1 B/F recombinant sequences obtained from a group of 587 patients under treatment failure from Argentina. To analyze the mosaic structures of these viral sequences and to determine their phylogenetic relationship, the 284 partial pol gene sequences of BF recombinant viruses were amplified by RT-PCR and sequenced. Intersubtype breakpoints were analyzed by bootscanning. Phylogenetic relationships were determined by means of neighbor-joining trees. The analysis of the sequences showed multiple phylogenetic topologies clustering within intersubtype BF reference sequences. At least three different mosaic patterns were found compared to previously described BF-type viruses with unequal distribution in the studied population. The analysis also showed that HIV-1 BF recombinant viruses with diverse mosaic structures are phylogenetically related in their F segments and in selected B fragments with the F1 subtype and with BF recombinant viruses from Brazil, respectively, suggesting a common recombinant ancestor. No association was observed between the prevalence of each mosaic pattern and the frequency of major drug-resistance mutations in PR and RT.     

Intentional nonadherence due to adverse symptoms associated with antiretroviral therapy

OBJECTIVE: To estimate the frequency and possible predictors of patient-mediated intentional alterations in antiretroviral medication regimens in direct response to symptoms associated with antiretroviral therapy use. DESIGN: Cross-sectional survey of a population-based dynamic cohort of antiretroviral recipients in a province-wide HIV drug treatment program, the only source of free-of-charge antiretroviral medications in the province of British Columbia. METHODS: Program participants voluntarily complete program surveys on an annual basis. Study subjects were those who responded to the annual treatment program survey between January 1 and November 1, 2001. Patients reported on the occurrence and severity of symptoms of 42 side effects of antiretroviral agents. Symptoms were classified into four subgroups based on whether they were considered subjective or objective and whether they would or would not prompt clinical action. For each of the four symptom categories, patients reported what their physician recommended in response to symptoms in that group and what the patient actually did in response to these same symptoms. Intentional nonadherence was defined as reporting either skipping or altering dosages of selective regimen components or temporary cessation of therapy that was not recommended by the physician in response to adverse drug effects in the past year. RESULTS: Of 638 study subjects, 70 (11%) reported intentional nonadherence with between 4% and 7.4% reporting this activity over the preceding year depending on the symptom group. Multivariate analysis revealed that a plasma viral load of <400 copies/mL (adjusted odds ratio [AOR], 0.35; 95% CI, 0.21-0.61) and completion of high school (AOR, 0.43; 95% CI, 0.24-0.78) were both inversely associated with intentional nonadherence. Those subjects reporting at least one severe symptom were more than twice as likely to report intentional nonadherence (AOR, 2.24; 95% CI, 1.16-4.33). Similarly, each additional symptom considered to be objective and to require clinical action was associated with a 25% increase in the risk of intentional nonadherence (AOR, 1.25; 95% CI, 1.10-1.43). CONCLUSION: Intentional nonadherence to antiretroviral therapy is common among persons experiencing therapy-related side effects. Although the type and severity of adverse effects impact intentional nonadherence, this activity occurs in relation to symptoms regardless of their strict clinical relevance.     

Virologic and immunologic response,clinical progression,and highly active antiretroviral therapy adherence

A growing body of evidence suggests that a high degree of adherence is required to achieve and maintain a successful virologic response both in the short and long term. This holds true despite the definition of adherence or how it is measured. Reported differences in the degree of adherence required are likely due to differences in study design, difficulty measuring patient adherence, patient population studied, and the antiretroviral regimen studied. Virologic suppression and immunologic response often go hand in hand, but the impact of adherence on change in CD4 count tends to be delayed and, therefore, less apparent than the impact on HIV viral load. Degree of adherence has also been shown to be associated with AIDS-related morbidity, mortality, and hospitalizations.     

Prevalence and correlates of untreated human immunodeficiency virus type 1 infection among persons who have died in the era of modern antiretroviral therapy

We evaluated all human immunodeficiency virus (HIV)-related deaths over the period 1 January 1995-31 December 2001 in a Canadian province in which all HIV care and antiretroviral therapy are provided free of charge. Persons who had received antiretroviral drugs before death were compared with those who had died without ever receiving HIV treatment, by fitting a logistic model. Overall, 1239 deaths were attributed to HIV infection during the study period. Of these, 406 (32.8%) occurred among persons who had never received any HIV treatment. In adjusted analyses, aboriginal ethnicity, female sex, and lower median income were negatively associated with receiving HIV treatment before death. Furthermore, among the 833 individuals who received treatment before death, only 379 (45.5%) received antiretroviral medication >or=75% of the time during their first year receiving therapy. The data demonstrate the need for novel interventions to expand HIV care to specific populations.     

Randomized,controlled study of the effects of a short course of prednisone on the incidence of rash associated with nevirapine in patients infected with HIV-1

OBJECTIVE: To examine the effect of 2 weeks of treatment with prednisone on the incidence of nevirapine-associated rash in HIV-1-infected patients receiving combination antiretroviral therapy. METHODS: This was a 24-week, prospective, randomized, open-label, international study. Patients were randomized to receive nevirapine plus open-label prednisone (40 mg once daily for 14 days) (n = 69) or nevirapine alone (n = 69). All patients received at least two other antiretroviral drugs. Nevirapine was administered at the lead-in dosage of 200 mg once daily. After the initial 2 weeks of the study, the nevirapine dosage was increased to 200 mg twice daily. RESULTS: During the first 6 weeks of treatment, rash was not reduced in the patients who received prednisone: prednisone treatment group, 23 (33%)/69; nonprednisone treatment group, 13 (19%)/69 (one-tailed Fisher exact test for prednisone reducing the incidence of rash, p =.984). There tended to be more severe rashes (7% versus 1%, respectively) and more therapy discontinuations due to rash (16% versus 9%, respectively) in the prednisone treatment group than in the nonprednisone treatment group. Risk factors for rash included higher pretreatment CD4 cell count, lower HIV-1 RNA level, female sex, and higher trough nevirapine concentrations. The prednisone treatment group had a marked increase in the median CD4 cell count in the first 2 weeks, which stabilized at a level similar to that in the nonprednisone treatment group. HIV-1 RNA responses were similar between the two groups. Treatment-naive patients had similar decreases in plasma HIV-1 RNA levels at week 24: approximately 2.3 log(10) copies/mL. CONCLUSIONS: This study demonstrated that 2 weeks of concomitant therapy with prednisone does not decrease the occurrence of nevirapine-associated rash. The use of prednisone is not recommended to prevent rash in patients receiving nevirapine. Prednisone administration had no adverse effects on the virological responses or on CD4 cell count changes at 24 weeks.     

Mammary intraepithelial neoplasia outgrowths (MINO): MINO and human ductal carcinoma <Emphasis Type="Italic">in situ</Emphasis>

Germ-line mutations in the BRCA1 tumour suppressor gene contribute to familial breast tumour formation, but there is no evidence for direct mutation of the BRCA1 gene in the sporadic form of the disease. In contrast, decreased expression of the BRCA1 gene has been shown to be common in sporadic tumours, and the magnitude of the decrease correlates with disease progression. BRCA1 expression is also tightly regulated during normal breast development. Determining how these developmental regulators of BRCA1 expression are co-opted during breast tumourigenesis could lead to a better understanding of sporadic breast cancer aetiology and the generation of novel therapeutic strategies aimed at preventing sporadic breast tumour progression.