Tenofovir plus didanosine as Nrti backbone in HIV-infected subjects.

Nucleoside reverse transcriptase inhibitors (NRTI) are essential components of highly active antiretroviral treatment (HAART). Although several combinations can be used as NRTI backbones, not all are associated with good virological and/or immunological results. In particular, some NRTI combinations should be avoided due to antagonism (zidovudine plus stavudine) or to high rate of toxicity (didanosine plus stavudine). Tenofovir (TDF) and didanosine (ddI) are among the more often prescribed NRTI for their convenient posology (one pill each per day), relatively high genetic barrier for resistance, quite acceptable safety profile and remarkable antiviral potency when such drugs have been used as single drug or in combinations with other NRTIs. However, antiretroviral regimens containing TDF and ddI have been associated with a high rate of virological failure in HIV-infected naïve patients due to possible drug-interactions. The virological efficacy of this backbone in HIV-infected, HAART pre-treated subjects, is still controversial. Aim of this review is to assess the possible role that antiretroviral regimens containing TDF and ddI can have in the treatment of HIV-positive subjects, focusing on their plasmatic and/or intracellular interactions to optimize the antiretroviral efficacy and minimize the toxicities of this combination.

Immunological and virological effects of structured treatment interruptions following exposure to hydroxyurea plus didanosine.

Both hydroxyurea (HU) and structured treatment interruptions (STI) have been investigated as therapeutic approaches to enhance immune responses in chronically HIV-infected individuals. HIV-specific T cell responses as well as T cell activation were analyzed longitudinally in 31 HIV-infected individuals who had been treated for the prior 12 months with didanosine (ddI) plus HU and thereafter completed three STI cycles consisting of 2 months off and 2 months on ddI-HU. Similar increases in plasma HIV-RNA were seen in each of the three cycles off therapy, whereas CD4 counts remained fairly stable along the study period. T cell activation paralleled the evolution of plasma HIV-RNA during the first STI cycle and waned afterward. At baseline most patients presented a high level of CD8+ responses to different HIV peptide pools and 23% of them had CD4+ responses to Gag and/or Env. The level of CD8+ responses against each pool was stable and did not increase during STI cycles, while CD4 responses tended to decline. However, the contribution of Nef-specific response to the total CD8 response tended to increase. In a multivariate model, both a higher baseline plasma HIV-RNA and a higher level of Nef-specific response contribution to the total CD8+ response were independently associated with lower plasma HIV-RNA increases during each of the three STI cycles. Nef-specific CD8+ responses might contribute to a better virological control of HIV replication following treatment interruptions in HIV-infected individuals and might be boosted by the immunomodulatory effect of HU.

Dose-dependent influence of didanosine on immune recovery in HIV-infected patients treated with tenofovir.

BACKGROUND: Antiretroviral therapy (ART) containing tenofovir disoproxil fumarate (TDF) and didanosine (ddI) has been associated with poor immune recovery despite virologic success. This effect might be related to ddI toxicity since ddI exposure is substantially increased by TDF. OBJECTIVE: To analyze whether immune recovery during ART with TDF and ddI is ddI-dose dependent. DESIGN AND METHODS: A retrospective longitudinal analysis of immune recovery measured by the CD4 T-cell slope in 614 patients treated with ART containing TDF with or without ddI. Patients were stratified according to the tertiles of their weight-adjusted ddI dose: low dose (< 3.3 mg/kg), intermediate dose (3.3-4.1 mg/kg) and high dose (> 4.1 mg/kg). Cofactors modifying the degree of immune recovery after starting TDF-containing ART were identified by univariable and multivariable linear regression analyses. RESULTS: CD4 T-cell slopes were comparable between patients treated with TDF and a weight-adjusted ddI-dose of < 4.1 mg/kg per day (n = 143) versus TDF-without-ddI (n = 393). In the multivariable model the slopes differed by -13 CD4 T cells/mul per year [95% confidence interval (CI), -42 to 17; P = 0.40]. In contrast, patients treated with TDF and a higher ddI dose (> 4.1 mg/kg per day, n = 78) experienced a significantly impaired immune recovery (-47 CD4 T cells/microl per year; 95% CI, -82 to -12; P = 0.009). The virologic response was comparable between the different treatment groups. CONCLUSIONS: Immune recovery is impaired, when high doses of ddI (> 4.1 mg/kg) are given in combination with TDF. If the dose of ddI is adjusted to less than 4.1 mg/kg per day, immune recovery is similar to other TDF-containing ART regimen.

Resistencia del virus de inmunodeficiencia humano (VIH) a zidovudina (AZT): análisis genotípico en cepas aisladas de pacientes chilenos / Resistance of human immunodeficiency virus (VIH) to zidovudine: genotypic analysis in strains isolated from chilean patients

Background: Resistance of HIV to AZT is the result of mutations in the pol gene that codifies the enzyme reverse transcriptase. Aim: To asses the resistance to antiretroviral drugs in Chhilean patients infected with HIV. Material and methods: The presence of mutations was searched in 22 patients infected with HIV. The emergence or persistence of these mutations was studiend in sequential samples of 19 patients. The presence of the mutation that confers resistance to didanosine (ddi) was studied in those subjects exposed to the drug. Polymerase chain reaction techniques were used to analyze mutations in codons 41, 70 and 215 of the pol gene (resistance to AZT) and the mutation in codon 71 (resistance to DDI). Results: On admission, none of the patients without previous exposure to AZT had drug resistance mutations. Seven of 12 patients (58.3 percent) that had received AZT had mutations in codon 215. In two, they were associated to a mutation in codon 41 and in two, to a mutation in codon 70. After a mean follow up of 14 months, 13 of 15 patients (86 percent) that received AZT had viral strains genotypically resistant to the drug. In nine of these, the resistance was associated with disease progression. None of the 10 patients that received DDI had the mutation in codon 74 that confers resistance to the drug. However, in one of these patients, that never receided AZT, virus with a mutation in codon 215 was detected. Conclusions: A high percentage of patients that have received monotheraphy with AZT have genotypic resistance to the drug. This resistance is associated with clinical and immunological derangement in 70 percent of these subjects

Inhibitory effect of 3'-azido-3'-deoxythymidine on proliferative responsiveness of CD8+ lymphocytes to interleukin-2.

Although several studies have shown that 3'-azido-3'-deoxythymidine (AZT) is not toxic for CD4+ lymphocytes, its effect on CD8+ cells has never been studied in a systematic way. We purified CD8+ cells from the peripheral blood mononuclear cells of both human immunodeficiency virus (HIV)-seronegative and HIV-infected individuals by means of magnetic beads that had been coated with monoclonal antibodies. We report that AZT, but not two other nucleosides tested, inhibited the interleukin-2-dependent proliferation of CD8+ lymphocytes in a dose-dependent manner. No such effect was observed with regard to CD4(+)-enriched populations. The AZT-mediated antiproliferative effect did not appear to be related to either the CD4+ count or to prior treatment with this drug in the case of HIV-seropositive subjects.