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Triple NRTI Regimen: Combivir+Tenofovir
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Reported by Jules Levin
At the 12th CROI, there were two studies presented with short0term 24 weeks results using a triple nuke regimen of AZT-3TC+Tenofovir. The results are worth reading.
"Early Virologic Response at 1-Month and 8-Month Median Follow-up of a New Triple NUC Combination (Zidovudine, Lamivudine, and Tenofovir) in 36 Antiretroviral-naive, HIV-1-infected Patients"
Poster 599. 12th CROI. Feb 22-25, 2005, Boston, MA. Authors: David Rey*, M Krebs, M Partisani, G Hess-Kempf, C Cheneau, M Priester, C Bernard-Henry, E de Mautort, and J M Lang
Hosp Univ, Strasbourg, France
Background: High rates of early virologic failure have been reported in naive patients receiving triple NUC combinations containing tenofovir (TDF), with either lamivudine (LAM) and didanosine, or LAM and abacavir (ABC). However, a daily zidovudine (ZDV), LAM, ABC, and TDF regimen showed acceptable virologic success rate, and the resistance pattern (less K65R or M184V) suggested a role of ZDV in resistance modulation in this quadruple NUC combination.
Methods: This pilot prospective cohort study was conducted in the HIV outpatient clinic at Strasbourg University Hospital. Treatment-naïve subjects were offered a fixed-dose combination of ZDV/LAM (300 mg/150 mg) twice daily, and TDF 300 mg daily. CD4 cells count and HIV-1 viral load were assessed at baseline, after 1 and 2 months of treatment, and then every 2 months. Early virologic response was evaluated after 1 or 2 weeks of treatment.
Results: Between April 2002 and September 2004, 36 patients were included (30 males, 6 females; median age of 39 years [22 to 73]); 2 had an AIDS diagnosis.
At baseline, median CD4 count was 230/mm3 (69 to 425/mm3), 13 subjects had CD4 < 200/mm3, median HIV-1 viral load was 4.9 log, about 100,000 c/ml (3.14 to > 5.89 log), and 16 had a viral load > 5 log. Median follow-up was 8 months (1 week to 27 months).
On treatment analysis showed a median HIV RNA decrease after 1 to 2 weeks of treatment of --1.57 log, and after 1 month of --2.36 log (first quartile, --1.44 to --2.06 log; fourth quartile, --2.69 to --3.18 log).
Of 29 patients, 26 had a viral load < 1000 copies/mL at month 1. At month 6, 18 of 20 (90%) had viral load < 50 copies/mL, as did 9 of 13 (69%) after 12 months. Median time to HIV RNA < 50 copies/mL was 2 months (1 to 24 weeks). Median CD4 count increase at month 6 was + 85/mm3.
Of 32 treatment interruptions, 5 (16%) occurred because of side effects (abdominal pain and nausea in 3 and anemia in 2, probably due to ZDV).
During the first 12 months of treatment, 4 viral failures occurred (due to poor compliance), 1 with K65R mutation, 2 with M184V + 2 or 3 TAMS, and 1 with 2 TAMS. Two of them successfully changed the ARV treatment; the others remained on ZDV + LAM + TDF, with low viral loads.
Conclusions: Combination of ZDV + LAM + TDF in treatment-naïve HIV-infected subjects induces a rapid and sustained HIV RNA decrease, associated with a good immunologic response and good safety profile. Despite recent recommendations on triple NUC drugs association, the results of this evaluation suggest that this triple NUC combination should be further evaluated.
24 Weeks First-Line AZT-3TC/Tenofovir in Africa
"Short-term Virologic Response (24 weeks) to a Triple Nucleoside/Nucleotide Analogue Regimen in Adults with HIV Infection in Africa within the DART Trial"
This study and the next abstract also related to DART but on anemia development, was presented as an oral talk in the session titled: "Diagnosis & Treatment of HIV Infection in Developing Countries"
Authors and Affiliations: Cissy Kityo Mutuluuza*1, S Walker2, P Kaleebu3, V Robertson4, R Enzama1, A Burke2, D Yirrell3, A Reid4, P Munderi3, D Gibb2, C Gilks5, P Mugyenyi1, H Grosskurth3, J Hakim4, D Pillay6, and the DART Trial
1Joint Clin Res Ctr, Kampala, Uganda; 2Med Res Council Clin Trials Unit, London, UK; 3Med Res Council/Uganda Virus Res Inst Prgm on AIDS, Entebbe, Uganda; 4Univ of Zimbabwe, Harare; 5Imperial Coll, London, UK; and 6Univ Coll, London, UK
Body:
Background: DART (Development of Anti-Retroviral Therapy in Africa) is a randomized trial of monitoring strategies and planned interruptions (after 24 weeks) in 3300 symptomatic ART-naive adults with CD4 < 200 cells/mm3 from 3 clinical sites (2 in Uganda, 1 in Zimbabwe). Of 3263 patients enrolled to October 1, 2004, 2466 (76%) have received zidovudine (ZDV)+lamivudine (3TC)+ tenofovir DF (TDF) first-line. As there are few viral load data on this regimen, we conducted a 24-week virology sub-study (n = 300).
Methods: Plasma HIV-1 RNA was retrospectively assayed at 0, 4, 12, and 24 weeks in 100 patients at each site (50 with baseline CD4 of 1 to 99 and 50 of 100 to 199 cells/mm3) using the Roche Amplicor assay. All assays have been performed in Africa under cross-site quality assurance. Here we present results from Ugandan patients, based on available samples (intention to treat).
Results: Of the 200 Ugandan adults, 68% were women, median age was 37 years, and median baseline CD4 100 cells/mm3 (IQR 36 to 144).
Median HIV RNA was 333,600 copies/mL (IQR 106,000 to 662,300 copies/mL), and mean 5.4 log10 copies/mL (SD 0.7).
At week 24 (n = 188), 54% achieved < 50 copies/mL and 72% < 400 copies/mL (intent to treat M = F 51% and 68%, respectively). Corresponding proportions were 14% and 40% at week 4 (n = 193), and 49% and 85% at week 12 (n =1 87). Mean decreases from baseline were 2.5, 3.6, and 3.5 log10 copies/mL at weeks 4, 12, and 24, respectively, and median CD4 increases 83 and 88 cells/mm3 at weeks 12 and 24.
Six patients died before 24 weeks: 2 died before 4 weeks, the other 4 had final HIV RNA before death of < 1000 copies/mL. At 12 and 24 weeks, 10% and 19% had HIV RNA >= 1000 copies/mL (6% and 15% >= 2000 copies/mL). In the preceding 12 weeks, 28 of 37 patients with HIV RNA >= 1000 copies/mL at week 24 had been off ART for > 1 week (n = 4), had incomplete adherence (n = 23), became pregnant (n = 3), or had severe adverse events, grade 3/4 adverse events, or other ART-modifying adverse events (n = 6) or malaria (n = 12). Preliminary 24 week data from 100 patients in Zimbabwe are similar.
Conclusions: Triple nucleoside regimens are highly relevant in resource limited settings: 27% of DART patients have a prior diagnosis of pulmonary or extra-pulmonary tuberculosis, the latter also being the third most frequently reported WHO grade 4 event after baseline. ZDV+3TC+TDF has good virological efficacy in advanced HIV disease, comparable to that reported after HAART introduction in equivalent industrialised populations, but against a background of intercurrent illnesses. Evaluation of genotypes in those with HIV RNA >= 1000 copies/mL at 24 weeks, and response to 48 weeks are ongoing.
"Severe Anemia and Associated Risk Factors following Initiation of ZDV-containing Regimens in Adults with HIV Infection in Africa within the DART Trial"
Authors and Affiliations: Francis Ssali*1, P Munderi2, A Reid3, S Walker4, W Stohr4, C Gilks5, and the DART Trial
1Joint Clin Res Ctr, Kampala, Uganda; 2Med Res Council/Uganda Virus Res Inst Prgm on AIDS, Entebbe, Uganda; 3Univ of Zimbabwe, Harare; 4Med Res Council Clin Trials Unit, London, UK; and 5Imperial Coll, London, UK
Background: Anemia is associated with poorer survival in HIV-positive patients in industrialized countries. Severe anemia occurs in 2 to 4% patients initiating zidovudine (ZDV)-based therapy, but little is known about incidence and risk factors in resource-limited countries.
Methods: DART is a randomized trial of monitoring strategies and planned treatment interruptions (after 24 weeks) in 3300 symptomatic ART-naive adults with CD4 count < 200 cells/mm3 from 3 sites (2 Uganda, 1 Zimbabwe). The first-line regimen is combivir plus either tenofovir DF, nevirapine, or abacavir. Full blood counts are performed at baseline, weeks 4 and 12, then every 12 weeks, and also if clinically indicated. We analyzed the prevalence of anemia at scheduled assessments, and considered sex, age, and baseline laboratory measurements as potential risk factors for ever developing grade 4 anemia (< 6.5 mg/dL) at any time-point using logistic regression in a global analysis (not by randomized groups).
Results: To July 2004, 2932 adults had been randomized (65% women; median age 37 years; 23% WHO stage 4; median baseline CD4 86), and median follow-up was 24 weeks (IQR 12 to 36). Of 2854 patients with baseline haemoglobin, 340 (12%) already had anaemia (Hb < 9.5 mg/dL), with 7 (0.2%) having grade 2 toxicity or higher (Hb < 8 mg/dL, a minor protocol violation). Following ART initiation, 610 (21%) patients developed a new episode of anemia (worsening, or new episode following resolution), and 161 (5.5%) developed new grade 4 anemia (12 having repeated distinct grade 4 episodes). The first grade 4 episode was identified a median of 12 weeks after ART initiation (IQR 8 to 17, range 2 to 40). Correspondingly, the prevalence of grade 4 anemia was 0.6%, 2.2%, 0.7%, 0.4%, and 0.3% at 4, 12, 24, 36, and 48 weeks, respectively. Based on concurrent MCV, 37% grade 4 anemias were microcytic, 27% normocytic, and 21% macrocytic (15% had no MCV). Women, and those with lower hemoglobin, lower CD4 count, and lower weight at baseline were all significantly more likely to develop grade 4 anemia (all p < 0.05). Baseline neutrophil count was not an additional predictor.
Conclusions: Although the incidence of grade 4 anemia in DART is higher than expected, this may be partly explained by a higher proportion of women, more advanced disease, and lower hemoglobin at baseline in DART compared to studies in industrialised countries, as well as greater risk of malaria.
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