Development of HIV with drug resistance after CD4 cell count-guided structured treatment interruptions in patients treated with highly active antiretroviral therapy after dual-nucleoside analogue treatment. SENC (Spanish efavirenz vs. nevirapine comparison) trial: a randomized, open-label study in HIV-infected naive individuals. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. Virologic, immunologic, clinical, safety, and resistance outcomes from a long-term comparison of efavirenz-based versus nevirapine-based antiretroviral regimens as initial therapy in HIV-1-infected persons. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Three- or four- versus two-drug antiretroviral maintenance regimens for HIV infection. Randomized, open-label, comparative trial to evaluate the efficacy and safety of three antiretroviral drug combinations including two nucleoside analogues and nevirapine for previously untreated HIV-1 Infection: the OzCombo 2 study. Antiretroviral treatment simplification with 3 NRTIs or 2 NRTIs plus nevirapine in HIV-1-infected patients treated with successful first-line HAART. Simplification with abacavir-based triple nucleoside therapy versus continued protease inhibitor-based highly active antiretroviral therapy in HIV-1-infected patients with undetectable plasma HIV-1 RNA.
For patients with human immunodeficiency virus (HIV) infection, structured treatment interruption (STI) is an attractive alternative strategy to continuous treatment, particularly in resource-restrained settings, because it reduces both side effects and costs. One major concern, however, is the development of resistance to antiretroviral drugs that can occur during multiple cycles of starting and stopping therapy.
                HIV genotypic drug resistance was investigated in 20 HIV-infected Thai patients treated with highly active antiretroviral therapy (HAART) and CD4 cell count-guided STI after dual nucleoside reverse-transcriptase inhibitor (NRTI) treatment. Resistance was tested at the time of the switch from dual-NRTI treatment to HAART and when HAART was stopped during the last interruption.
                After STI, one major drug-resistance mutation occurred (T215Y), and, in the 4 samples with preexisting major mutations (D67N [n=2], K70R [n=2], T215Y [n=2], and T215I [n=1]), the mutations disappeared. All mutations in the HIV protease gene were minor mutations already present, in most cases, before STI was started, and their frequency was not increased through STI, whereas the frequency of reverse-transcriptase gene mutations significantly decreased after the interruptions. After the 48-week study period, no patients had virological failure. Long-term follow-up (108 weeks) showed 1 case of virological failure in the STI arm and 1 in the continuous arm. No virological failure was seen in patients with major mutations.
                Major HIV drug-resistance mutations were not induced through CD4 cell count-guided treatment interruptions in HIV-infected patients successfully treated with HAART after dual-NRTI therapy. A randomized, open-label, pilot study was undertaken to explore the antiviral activity and tolerability of two nonnucleoside reverse transcriptase inhibitors (NNRTIs), nevirapine (NVP) and efavirenz (EFV).
                HIV-infected antiretroviral-naive adults with CD4 counts >100 cells/mm(3) and detectable plasma HIV RNA below 100,000 copies/mL were randomized to receive didanosine (ddI) and stavudine (d4T) plus either NVP or EFV. Assessments were made every 12 weeks. Primary endpoints were the proportion of patients reaching plasma HIV RNA <50 copies/mL and/or developing NNRTI-related toxicities leading to drug discontinuation. Baseline characteristics were comparable for participants in the EFV (n = 31) and NVP arms (n = 36).
                At 48 weeks, 23/31 (74%) patients in the EFV group and 23/36 (64%) in the NVP group had <50 HIV RNA copies/mL (intention-to-treat analysis). Adverse events led to NNRTI discontinuation in 4 and 3 patients in the EFV and NVP arms, respectively. There were no statistically significant differences between groups regarding any primary endpoint. NVP and EFV along with two NRTIs may be equally well tolerated and effective at achieving <50 HIV RNA copies/mL in naive patients with CD4 counts >100 cells/mm(3) and HIV RNA <10(5) copies/mL.
                A much larger study is needed to demonstrate any significant differences between NVP and EFV, if they exist at all. Regimens containing three nucleoside reverse-transcriptase inhibitors offer an alternative to regimens containing nonnucleoside reverse-transcriptase inhibitors or protease inhibitors for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection, but data from direct comparisons are limited.
                This randomized, double-blind study involved three antiretroviral regimens for the initial treatment of subjects infected with HIV-1: zidovudine-lamivudine-abacavir, zidovudine-lamivudine plus efavirenz, and zidovudine-lamivudine-abacavir plus efavirenz.
                We enrolled a total of 1147 subjects with a mean baseline HIV-1 RNA level of 4.85 log10 (71,434) copies per milliliter and a mean CD4 cell count of 238 per cubic millimeter were enrolled. A scheduled review by the data and safety monitoring board with the use of prespecified stopping boundaries led to a recommendation to stop the triple-nucleoside group and to present the results in the triple-nucleoside group in comparison with pooled data from the efavirenz groups. After a median follow-up of 32 weeks, 82 of 382 subjects in the triple-nucleoside group (21 percent) and 85 of 765 of those in the combined efavirenz groups (11 percent) had virologic failure; the time to virologic failure was significantly shorter in the triple-nucleoside group (P<0.001). This difference was observed regardless of the pretreatment HIV-1 RNA stratum (at least 100,000 copies per milliliter or below this level; P< or =0.001 for both comparisons). Changes in the CD4 cell count and the incidence of grade 3 or grade 4 adverse events did not differ significantly between the groups.
                In this trial of the initial treatment of HIV-1 infection, the triple-nucleoside combination of abacavir, zidovudine, and lamivudine was virologically inferior to a regimen containing efavirenz and two or three nucleosides.
                Copyright 2004 Massachusetts Medical Society To compare long-term virologic, immunologic, and clinical outcomes in antiretroviral-naïve persons starting efavirenz (EFV)- versus nevirapine (NVP)-based regimens.
                The FIRST study randomized patients into three strategy arms: PI+NRTI, NNRTI+NRTI, and PI+NNRTI+NRTI. NNRTI was determined by optional randomization (NVP or EFV) or by choice. For this randomized substudy, the primary endpoint was HIV RNA >50 copies/mL after 8 months or death. Genotypic resistance testing was done at virologic failure (VF; HIV RNA >1,000 copies/mL at or after 4 months).
                228 persons (111 randomized to EFV, 117 to NVP) were followed for median 5 years. Rates per 100 person years for the primary endpoint were 41.2 (EFV) and 42.8 (NVP; p = .59). The percent of persons with HIV RNA <50 copies/mL was similar throughout follow-up (p = .24), as were average increases in CD4+ cells (p = .30). 423 persons declining the substudy chose EFV; 264 chose NVP. There were 915 persons in the combined cohort (randomized and choice). In the combined cohort, the risk of VF and VF with any NNRTI or NRTI resistance or resistance of any class was significantly less for EFV compared to NVP.
                EFV-based regimens as initial therapy resulted in a lower risk of VF and VF with resistance than did NVP-based regimens, although immunologic and clinical outcomes were similar. The 2NN Study was a randomised comparison of the non-nucleoside reverse-transcriptase inhibitors (NNRTI) nevirapine and efavirenz.
                In this multicentre, open-label, randomised trial, 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine, for 48 weeks. The primary endpoint was the proportion of patients with treatment failure (less than 1 log(10) decline in plasma HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards, disease progression [new Centers for Disease Control and Prevention grade C event or death], or change of allocated treatment). Analyses were by intention to treat.
                Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz. The difference between nevirapine twice daily and efavirenz was 5.9% (95% CI -0.9 to 12.8). There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p=0.193) or the increases in CD4-positive cells (p=0.800). Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine.
                Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regimens with either NNRTI are valid for first-line treatment. There are, however, differences in safety profiles. Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events. Combination antiretroviral therapy administered to HIV-infected individuals has been shown to improve immunologic function and delay the progression of HIV infection. However, because patient adherence to complicated combination-therapy antiretroviral regimens is difficult and because of concerns regarding cumulative toxicity of antiretroviral drugs, regimens that utilize fewer antiretroviral agents are desirable.
                To compare the use three- or four- versus two-drug antiretroviral maintenance regimens following successful induction therapy for HIV infection.
                The following electronic databases were searched for relevant randomized trials or reviews: 1. MEDLINE for the years 1982-1999 using the search terms human immunodeficiency virus, antiretroviral therapy, maintenance therapy, zidovudine, lamivudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, AIDS, anti-HIV agents, HIV infection and HIV seropositivity 2. AIDSLINE for the years 1982-1999 using the search terms antiretroviral therapy, maintenance therapy, zidovudine, lamidvudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, anti-HIV agents 3. The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Clinical Trials Register in the Cochrane Library, Issue 2, 1999. 4. The specialist register of trials maintained by the Cochrane Collaborative Review Group on HIV Infection and AIDS 5. AIDSTRIALS, a specialist registry of current and completed trials maintained by the U.S. National Library of Medicine The abstracts of relevant conferences, including the International Conferences on AIDS, the Conference on Retroviruses and Opportunistic Infections, the Infectious Disease Society of America annual meeting and the Interscience Conference on Antimicrobial Agents and Chemotherapy, as indexed by AIDSLINE, were also reviewed. All reference lists of all review articles and primary articles identified were searched.
                Randomized controlled trials in which HIV-infected adults who had successfully completed three- or four-drug antiretroviral induction therapy were randomized to maintenance therapy with three or four drugs or maintenance therapy with two drugs. Successful induction therapy was defined by a plasma viral load of less than 500 copies/ml.
                Two reviewers assessed eligibility and trial quality. Attempts were made to contact the authors of the included abstract. Data on the number of patients experiencing loss of viral suppression were abstracted by two reviewers. The data were pooled, where appropriate, to yield odds ratios, using random effects models.
                Four trials were identified including three published studies and one abstract. Compared to three- or four-drug maintenance therapy, maintenance therapies including fewer drugs were associated with a higher risk of virologic failure (loss of HIV suppression to non-detectable levels). Combining the results of all four studies yielded an odds ratio of 5.55 (95% confidence interval, 3.14 - 9.80). Similar results were obtained when the one abstract was excluded (odds ratio, 5.48; 95% confidence interval, 2.82 - 10.65). Performing subgroup analyses of studies using the same induction and maintenance regimens gave similar results. Maintenance regimens of zidovudine and lamivudine compared to maintenance regimens with zidovuine, lamivudine and indinavir, were associated with significantly higher rates of virologic failure (odds ratio, 4.57; 95% confidence interval, 1.80 - 11.58). Similarly, maintenance regimens that discontinued one or more protease inhibitor after including them in induction therapy were also associated with a significantly higher risk of virologic failure (odds ratio, 6.15; 95% confidence interval, 3.40 -11.10). (ABSTRACT TRUNCATED) To assess and compare the efficacy and safety of three triple combination antiretroviral therapies in HIV-1-infected treatment-naive patients.
                Seventy treatment-naive HIV-infected adults with CD4+ T-cell counts >50/microL were randomized to receive either zidovudine + lamivudine + nevirapine (AZT + 3TC + NVP), stavudine + didanosine + nevirapine (d4T+ddI+NVP), or stavudine + lamivudine + nevirapine (d4T+3TC+NVP) for 52 weeks. Patient assessments were conducted monthly and included measurement of plasma HIV RNA levels and CD4+ T-cell counts and evaluations for drug toxicity.
                The mean time-weighted reductions in plasma HIV RNA in the AZT+3TC+NVP, d4T+3TC+NVP, and d4T+ddI+NVP groups were 1.29, 2.13, and 1.78 log(10) copies/mL, respectively (p =.389). The proportions of patients with HIV RNA <50 copies/mL in the AZT+3TC+NVP, d4T+3TC+NVP, and d4T+ddI+NVP groups were 73%, 68%, and 80%, respectively (p =.71). The mean time-weighted increases in CD4+ T-cell counts in the AZT+3TC+NVP, d4T+3TC+NVP, and d4T+ddI+NVP groups were 139, 113, and 174 cells/microL, respectively (p =.30). Three patients ceased assigned treatment due to rash (one from each treatment arm), and 5 of the 45 patients on d4T (3 from the d4T+3TC+NVP arm and 2 from the d4T+ddI+NVP arm) ceased assigned treatment due to neuropathy.
                All three-drug combinations were equally effective at suppressing viral load and increasing CD4+ T-cell counts. No significant differences were detected between the treatment groups in virological or immunological response or cessation of study drugs due to adverse events, although it is possible that the study was underpowered to detect differences. NVP was safe and efficacious in this setting, and efficacy was not influenced by nucleoside reverse transcriptase inhibitor backbone. To assess the virologic noninferiority of an antiretroviral treatment simplification with coformulated zidovudine/lamivudine/abacavir (group 1) vs. coformulated zidovudine/lamivudine plus nevirapine (group 2) in HIV-1-infected patients receiving successful first-line highly active antiretroviral therapy.
                This is a prospective, multicenter, open-label, comparative, randomized, noninferiority study. A delta of 15% for differences in virologic suppression <200 copies/mL between groups was prespecified with a 1-sided 0.025 significance level.
                A total of 134 patients were included into this study: 68 were allocated to group 1 and 66 to group 2. By intention-to-treat analysis (switch equals failure), the percentage of virologic suppression <200 copies/mL (<50 copies/mL) at week 48 was 71.0% (65.1%) and 73.0% (63.3%) in groups 1 and 2, respectively (estimate for differences [<200 copies/mL]: -2.1, 95% CI: -17.4-13.1, P=0.783). Thirteen and 14 patients in groups 1 and 2, respectively, discontinued therapy due to adverse events. Dyslipidemia improved in both groups, with a higher improvement in low-density lipoprotein cholesterol (P=0.049) in group 1.
                Group 1 is not inferior to group 2 regarding virologic suppression <200 copies/mL. Both strategies improve lipid profile. To assess the antiviral efficacy, safety and adherence in patients switched to an abacavir-containing nucleoside reverse transcriptase inhibitor (NRTI) regimen after long-term HIV-1 RNA suppression with a dual NRTI/protease inhibitor (PI) combination.
                In an open-label, multicentre study, patients receiving 2NRTI plus PI for at least 6 months, with a history of undetectable plasma HIV-1 RNA since the initiation of therapy and plasma HIV-1 RNA < 50 copies/ml at screening, were randomly assigned to replace the PI with abacavir (n = 105) or continue the same treatment (n = 106). Clinical assessments included plasma HIV-1 RNA, chemistry, haematology, lymphocyte counts, and adverse event reports. Adherence to treatment was assessed by patient self-report.
                A significantly longer time to treatment failure was demonstrated in the abacavir arm compared with the PI arm (P = 0.03) while treatment failure was experienced by significantly more patients in the PI arm: 24 (23%) versus 12 (12%) (P = 0.03). Therapy-limiting toxicity led to treatment failure in eight versus 14 cases in the abacavir and PI arms, respectively, whereas virological rebound was the cause in four versus two cases. Significant reductions in cholesterol and non-fasting triglyceride plasma levels at 48 weeks were observed in the abacavir arm (P < 0.001 andP = 0.035, respectively). The number of patients reporting no difficulty in taking their therapy showed a marked increase from baseline in the abacavir arm.
                The replacement of PI by abacavir in a triple combination regimen following prolonged suppression of plasma HIV-1 RNA provides continued virological suppression, significant improvements in lipid abnormalities and enhanced ease of dosing.
Both drugs have equivalent efficacies in initial treatment of HIV infection when combined with two NRTIs, but different side effects.