A randomized, open-label, comparative trial of zidovudine plus lamivudine versus zidovudine plus lamivudine plus didanosine in antiretroviral-naive HIV-1-infected Thai patients.

OBJECTIVE: To assess the efficacy and tolerability of a triple nucleoside reverse transcriptase inhibitor combination of zidovudine, lamivudine, and didanosine therapy. DESIGN: A randomized open-label trial. PATIENTS: Antiretroviral-naive HIV-infected patients with CD4+ cell counts of 100 to 500 cells/microl. METHODS: A total of 106 patients were randomly assigned to 300 mg of zidovudine (200 mg for body weight <60 kg) twice daily plus 150 mg of lamivudine twice daily plus 200 mg of didanosine (125 mg for body weight <60 kg) twice daily (n = 53) or to zidovudine plus lamivudine (n = 53) for 48 weeks. MAIN OUTCOME MEASURES: Degree and duration of reduction of HIV-1 RNA load and increase in CD4+ cell counts from baseline and development of drug-related toxicities. RESULTS: At 48 weeks, triple drug therapy showed greater declines in plasma HIV-RNA levels from the beginning of treatment than double drug therapy (1.86 vs. 1.15 log10 copies/ml, respectively; p <.001). The proportions of patients with HIV-RNA <50 copies/ml in an intention-to-treat analysis were 54.7% (29 of 53 patients) and 11.3% (6 of 53 patients) in the triple and double drug therapy, respectively (p =.001). There was no significant difference in increase of CD4 count. CONCLUSION: Triple drug therapy with zidovudine, lamivudine, and didanosine was significantly more effective in inducing sustained immunologic and virologic responses than the double combination of zidovudine and lamivudine.

A randomized, double-blind trial of half versus standard dose of zidovudine plus zalcitabine in Thai HIV-1-infected patients (study HIV-NAT 001). HIV Netherlands Australia Thailand Research Collaboration.

BACKGROUND: Triple combination antiretroviral therapy, recommended as standard of care, is unaffordable for much of the developing world. OBJECTIVES: To establish whether half doses of zidovudine (AZT) and zalcitabine (ddC) are as effective as standard doses in a Thai population with lower body weight than Western populations and predominantly infected with HIV-1 subtype E. METHODS: A group of 116 antiretroviral naive patients, with CD4 cell counts 100-500 x 10(6) cells/l, were randomized to: AZT 200 mg three times daily plus ddC 0.75 mg three times daily versus AZT 100 mg three times daily plus ddC 0.375 mg three times daily and followed-up regularly for 48 weeks. RESULTS: The study enrolled 111 patients: 59 men and 52 women, body weight (mean +/- standard deviation) 56.4 +/- 12.3 kg, mean CD4 cell count 324 x 10(6) cells/l, mean HIV RNA 4.7 log10 copies/ml. There were no significant differences between the two groups. Twelve patients discontinued, including two deaths that were unrelated to study medication. No significant differences in adverse events were seen. Week 48 data for the standard dose and half dose arms, respectively, were mean CD4 cell count increases of 52 and 78 x 10(6) cells/l (P = 0.34), mean plasma HIV-1 RNA reduction of 1.4 and 1.1 log10 copies/ml (P = 0.10), HIV RNA of < 400 copies/ml in 52 and 20%[ (P = 0.001). Participants with higher than mean baseline CD8 cell counts (mean 1062 x 10(6) cells/l) showed greater decline in CD8 cells on standard doses. Further analysis showed improved reduction in HIV RNA (P < 0.0001) and in the percentage with undetectable HIV RNA (P = 0.0137) in the standard dose arm, corrected for baseline HIV RNA, which if < 4.75 log10 copies/ml significantly correlated with HIV RNA < 400 copies/ml at week 48. CONCLUSION: At week 48, the proportion with HIV RNA < 400 copies/ml was significantly higher in the standard dose arm; lower baseline HIV RNA correlated with better HIV RNA outcome at 48 weeks. The arms did not differ in CD4 cell response but standard doses correlated with greater CD8 cell decline.

A randomized, dose-finding study with didanosine plus stavudine versus didanosine alone in antiviral-naive, HIV-infected Thai patients.

OBJECTIVES: To evaluate the safety and efficacy of four different regimens of didanosine (ddI) + stavudine (d4T) in HIV-infected Thais. DESIGN: Prospective, open-label, randomized study. METHODS: Patients were randomized to four regimens of high and low doses of ddI and d4T or to ddI alone. D4T was added to the ddI-alone arm after week 24. The duration of study was 48 weeks. RESULTS: Seventy-eight patients were randomized (mean CD4 cell count, 255 x 10(6)/l; mean plasma HIV-1 RNA; 4.3 log10 copies/ml). In the intent-to-treat analysis, 78% of patients in the pooled combination arms and 20% of the patients in the ddI alone arm (to which d4T was added after 24 weeks) showed plasma HIV-1 RNA < 500 copies/ml at week 24 (P < 0.001), and 59% versus 53% at week 48, respectively. In addition, the proportion of patients with < 50 HIV-1 RNA copies/ml was 13% versus 7% at week 24 (P = 0.5) and 17% versus 20% at week 48 respectively. At week 24, median CD4 cell count increases from baseline were 101 x 10(6)/l in the pooled combination versus 76 x 10(6)/l in the ddI alone arm (P = 0.78). Logistic regression modeling suggested a correlation between receiving high dose ddI and achieving HIV-1 RNA < 500 copies/ml at week 48 (P = 0.07). CONCLUSIONS: The d4T/ddI combination was superior to ddI alone in producing HIV-1 viral suppression. At week 48, > 60% of patients treated with this combination reached HIV-1 RNA levels < 500 copies/ml. Receiving high dose ddI but not d4T may correlate with a better viral suppression.

Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. INCAS Study Group.

BACKGROUND: Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. OBJECTIVES: In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. METHODS: Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and naïve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). RESULTS: Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naïve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the naïve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of naïve CD4+ T cells at baseline resulted in modest long-term naïve T-cell recovery. CONCLUSIONS: Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Naïve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported for immune recovery in adults after chemotherapy and bone marrow transplantation.

Cell cycle effects and concomitant p53 expression in hairless murine skin after longwave UVA (365 nm) irradiation: a comparison with UVB irradiation.

Ultraviolet A (UVA, 315-400 nm) radiation is known to be a complete carcinogen, but in contrast to UVB (280-315 nm) radiation, much of the cell damage is oxygen dependent (mediated through reactive oxygen species), and the dominant premutational DNA lesion(s) remains to be identified. To investigate further the basic differences in UVA and UVB carcinogenesis, we compared in vivo cellular responses, viz. cell cycle progression and transient p53 expression in the epidermis, after UVA1 (340-400 nm) exposure with those after broadband UVB exposure of hairless mice. Using flow cytometry we found a temporary suppression of bromodeoxyuridine (BrdU) uptake in S-phase cells both after UVB and UVA1 irradiation, which only in the case of UVB is followed by an increase to well over control levels. With equally erythemogenic doses (1-2 MED), the modulation of BrdU uptake was more profound after UVB than after UVA1 irradiation. Also, a marked transient increase in the percentage of S-phase cells occurred both after UVB and after UVA1 irradiation, but this increase evolved more rapidly after UVA1 irradiation. Further, p53 expression increased both after UVB and UVA1 irradiations, with peak expression already occurring from 12 to 24 h after UVA1 exposure and around 24 h after UVB exposure. Overall, UVA1 radiation appears to have less of an impact on the cell cycle than UVB radiation, as measured by the magnitude and duration of changes in DNA synthesis and cells in S phase. These differences are likely to reflect basic differences between UVB and UVA1 in genotoxicity and carcinogenic action.