A simple, once-daily dosing regimen for treating HIV-1 infection in intravenous drug users.
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Anti-HIV Agents↗
Biomedical subjects
S Staszewski
Publications and source records attributed to S Staszewski.
A case of lipodystrophy after the initiation of zidovudine, lamivudine and efavirenz in an asymptomatic HIV-1-infected patient.
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Abdomen↗
Resistance profiles in patients with viral rebound on potent antiretroviral therapy.
The prevalence of phenotypic drug resistance was assessed in 60 patients with a viral rebound after they received a protease inhibitor (PI)- or nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing regimen (baseline). Resistance testing was done within 36 weeks of viral rebound; no resistance testing was available at baseline. All patients had previously received zidovudine; 86.0% had received lamivudine. In total, 45.1% of the patients had strains resistant to the PI that they started and 88.9% given nevirapine had strains with reduced susceptibility to that drug. Overall, 46 patients (76.7%) harbored a strain resistant to >/=1 drug of their initial PI- or NNRTI-containing regimen. Of 53 patients who remained on treatment at the time of the study (40 had switched to a different combination from that at baseline), 6 harbored isolates susceptible to all drugs they had ever received. Thus, patients with viral rebound while on potent antiretroviral therapy usually have reduced susceptibility to >/=1 drug. Viral rebound also occurs in persons in whom resistant strains could not be detected by the assay used.
Drug Resistance↗
Predicting the duration of antiviral treatment needed to suppress plasma HIV-1 RNA.
Effective therapeutic interventions and clinical care of adults infected with HIV-1 require an understanding of factors that influence time of response to antiretroviral therapy. We have studied a cohort of 118 HIV-1-infected subjects naive to antiretroviral therapy and have correlated the time of response to treatment with a series of virological and immunological measures, including levels of viral load in blood and lymph node, percent of CD4 T cells in lymph nodes, and CD4 T-cell count in blood at study entry. Suppression of viremia below the limit of detection, 50 HIV-1 RNA copies/mL of plasma, served as a benchmark for a successful virological response. We employed these correlations to predict the length of treatment required to attain a virological response in each patient. Baseline plasma viremia emerged as the factor most tightly correlated with the duration of treatment required, allowing us to estimate the required time as a function of this one measure.
Adult↗
HIV drug susceptibility and treatment response to mega-HAART regimen in patients from the Frankfurt HIV cohort.
OBJECTIVE: To assess the relationship between viral susceptibility at baseline and virological response in human immunodeficiency virus (HIV)-infected patients treated with multi-drug salvage regimens after multiple previous treatment failures. DESIGN: Retrospective analysis of 50 patients from the Frankfurt HIV cohort who had received treatment with a minimum of six drugs, and for whom a sample for baseline viral phenotyping was available. METHODS: Viral drug susceptibility was measured retrospectively from stored samples using the Antivirogram, a recombinant virus assay based method. Virological response was defined as a viral load of < 400 copies/ml at week 24. For analysis of treatment response, drop-outs were dealt with in two ways, either as failures (DAF) or censored (DAC). Several logistical regression models were applied to identify predictors of response, including baseline virus load, number of new drugs and phenotypic sensitivity scores. RESULTS: At baseline, drug resistance was extensive: 96% of patients had viruses resistant to at least one drug class and 32% had viruses resistant to all three drug classes. In the DAF analysis, 39 patients experienced virological failure. In the DAC analysis, eight were censored and 31 patients experienced virological failure. In multivariate models that adjust for baseline viral load, the number of new drugs and total phenotypic sensitivity scores, the baseline viral load and phenotypic sensitivity score remained significantly associated with virological outcome, whereas in those adjusted for baseline viral load, the number of new drugs, NRTI phenotypic sensitivity score and PI phenotypic sensitivity score, only the latter remained significantly associated with virological outcome. Both the DAF and DAC analyses produced similar results. In all models used, virological failure was shown to be significantly associated with baseline viral load and phenotypic sensitivity score. CONCLUSIONS: In this retrospective analysis based on a small number of patients, viral drug susceptibility at baseline was strongly associated with virological outcome at 24 weeks, independent of covariates such as baseline viral load and treatment history. Baseline viral load also maintained a significant, independent association with virological outcome in most models.
Anti-HIV Agents↗
Cervical intraepithelial neoplasia in human immunodeficiency virus-positive patients.
Cervical intraepithelial neoplasia (CIN) is common in patients positive for human immunodeficiency virus (HIV). The questions are whether the management of CIN in these patients should be different from that of HIV-negative women, whether there are any prognostic factors to indicate the course of CIN, and whether the latter is influenced by antiretroviral therapy. A total of 267 HIV-seropositive women were counseled and examined in our colposcopic clinic. Of that number, 53 patients died during the observation period; 74% of these patients were immunosuppressed (CD4 count < 200 cells/mm3), and 45% were given diagnoses of CIN. The incidence of CIN was significantly higher in patients with CD4 less than 200 cells/mm3. Neither the route of HIV infection nor the HPV status nor smoking habits correlated with CIN. CIN relapse was histologically confirmed in 28% of patients who underwent complete surgical removal. Immune status plays an important role in HIV-positive women not only with respect to survival but with respect to CIN.
Adult↗
Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team.
BACKGROUND: Efavirenz is a nonnucleoside reverse-transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). We compared two regimens containing efavirenz, one with a protease inhibitor and the other with two nucleoside reverse-transcriptase inhibitors, with a standard three-drug regimen. METHODS: The study subjects were 450 patients who had not previously been treated with lamivudine or any nonnucleoside reverse-transcriptase inhibitor or protease inhibitor. In this open-label study, patients were randomly assigned to one of three regimens: efavirenz (600 mg daily) plus zidovudine (300 mg twice daily) and lamivudine (150 mg twice daily); the protease inhibitor indinavir (800 mg every eight hours) plus zidovudine and lamivudine; or efavirenz plus indinavir (1000 mg every eight hours). RESULTS: Suppression of plasma HIV-1 RNA to undetectable levels was achieved in more patients in the group given efavirenz plus nucleoside reverse-transcriptase inhibitors than in the group given indinavir plus nucleoside reverse-transcriptase inhibitors (70 percent vs. 48 percent, P<0.001). The efficacy of the regimen of efavirenz plus indinavir was similar (53 percent) to that of the regimen of indinavir, zidovudine, and lamivudine. CD4 cell counts increased significantly with all combinations (range of increases, 180 to 201 cells per cubic millimeter). More patients discontinued treatment because of adverse events in the group given indinavir and two nucleoside reverse-transcriptase inhibitors than in the group given efavirenz and two nucleoside reverse-transcriptase inhibitors (43 percent vs. 27 percent, P=0.005). CONCLUSIONS: As antiretroviral therapy in HIV-1-infected adults, the combination of efavirenz, zidovudine, and lamivudine has greater antiviral activity and is better tolerated than the combination of indinavir, zidovudine, and lamivudine.
Adult↗
Determinants of sustainable CD4 lymphocyte count increases in response to antiretroviral therapy.
OBJECTIVE: HIV-induced CD4 lymphocyte depletion is partially reversed by antiretroviral therapy but it is unclear if the degree to which the CD4 count rises depends on viral suppression (if so, the extent of viral suppression required to achieve a maximal CD4 count rise), whether the rise is sustainable and whether it occurs in patients with CD4 count <10 x 10(6) cells/l. We aimed to address these issues. METHODS: We studied CD4 count and plasma HIV RNA values every 4 weeks for 72 weeks in 154 patients starting indinavir-containing regimens. RESULTS: Mean baseline HIV RNA and CD4 count were 4.8 log10 copies/ml and 180 x 10(6) cells/l, respectively. Overall, there was a mean increase in CD4 count of 143 x 10(6) cells/l by 72 weeks. The adjusted mean increase (adjusted for initial viral load, CD4 count and age) was strongly related to the mean viral suppression over the follow-up period (P < 0.0001). Importantly, there was a highly significant difference (P = 0.0004) in the rise in CD4 count between those with 2-3 log suppression (161 x 10(6) cells/l) and those with > 3 log suppression (314 x 10(6) cells/l; mean 3.6 log suppression in this group), suggesting that with even greater suppression the rise in CD4 lymphocytes may be still larger. We also studied whether CD4 counts were still rising after 72 weeks in patients with sustained suppression of at least 3 log in viral load. There was a significant (P = 0.004; paired t-test) rise in count of 43 x 10(6) cells/l between weeks 64 and 72 in these patients, suggesting that regeneration continues at least up to 72 weeks after therapy, provided virus replication continues to be suppressed. Patients with initial CD4 counts < 10 x 10(6) cells/l experienced no smaller rises than those at higher levels, even after adjustment for other factors. CONCLUSION: These results strongly support a direct causal relationship between HIV replication and CD4 lymphocyte count depletion. The rise in those with > 3 log suppression provides the best available indicator of the potential for natural CD4 regeneration in HIV-infected patients. However, since still greater CD4 count rises may be seen with more suppressive regimens, it may not be possible to study the intrinsic CD4 regenerative capacity until such regimens are available.
Adult↗
Pneumocystis carinii pneumonia in the Federal Republic of Germany in the era of changing antiretroviral therapy - IDKF 13 -. German AIDS Study Group (GASG/IdKF).
BACKGROUND: Pneumocystis carinii pneumonia (PCP) is one of the most common AIDS defining diagnoses. METHODS: In a prospective observational trial all cases of Pneumocystis carinii pneumonia (PCP) were evaluated. Patients with and without PCP-prophylaxis were compared for symptoms, efficacy, side effects and mortality at week 4 and 26. RESULTS: 293 patients developed a PCP episode. Patients with no prophylaxis had a significant lower CD4 cell count and a more severe clinical status at time of diagnosis. This was pronounced in the group with first positive HIV test at time of diagnosis. There was no difference in the rate of successful treatment between both groups. At week four a tendency to a better survival in the group with prophylaxis was observed, however this changed to a trend to a better survival at week 26 for the group without prophylaxis. CONCLUSION: Even in the era of highly active antiretroviral treatment many patients present with PCP. Nearly 60% of patients presented without antiretroviral treatment or PCP-prophylaxis. Nearly 25% of all patients had their first HIV-test at time of PCP diagnosis.
AIDS-Related Opportunistic Infections↗
Virological response to protease inhibitor therapy in an HIV clinic cohort.
OBJECTIVE: New antiretroviral strategies aim to reduce plasma HIV RNA (viral load) to below the limits of detectability of assays with the objective of reducing viral replication in order to stop or reverse the pathogenic process and prevent development of drug resistance. First use of a protease inhibitor might offer the most realistic chance of achieving this aim. Our objective was to study the virological response to protease inhibitors in patients taking them for the first time. METHODS: A total of 901 patients from a large outpatient clinic were followed a mean of 15 months from the time of starting a protease inhibitor until 1 May 1998. Viral load and CD4 cell count measurements were made on average every 34 days. RESULTS: Overall there was a 79% [95% confidence interval (CI), 76-82] probability of the patients achieving a viral load < 500 copies/ml by 24 weeks after starting the protease inhibitor. In a multiple Cox regression model, those with lower initial viral load [relative hazard (RH), 0.72; P < 0.0001], higher CD4 cell count (RH, 1.07; P = 0.002), those starting other new drugs at same time as the protease inhibitor (RH, 1.46 for two versus none; P = 0.003), those who were antiretroviral-naive, and those using indinavir or nelfinavir were more likely to achieve such levels. In those 651 patients achieving viral load < 500 copies/ml within 24 weeks, there was an estimated 53% (95% CI, 51-55) probability of rebound of viral load to > 500 copies/ml by 52 weeks from the first undetectable value. Again, those who had started other new drugs at the same time as the protease inhibitor (RH, 0.57; P = 0.003 for starting two versus none) tended to experience a lower probability of viral load rebound, as did those with higher initial CD4 cell count (RH, 0.87 per 100 x 10(6)/l higher; P = 0.0007). Those who took saquinavir achieved less durable virological responses than those who took other protease inhibitors. CONCLUSIONS: Starting protease inhibitor therapy with two other new antiretroviral drugs simultaneously with protease inhibitor therapy offers a better best chance of achieving sustained viral load < 500 copies/ml than starting fewer new drugs.
Adult↗
Risk of new AIDS diseases in people on triple therapy.
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Acquired Immunodeficiency Syndrome↗
Efficacy and safety of combination therapy with delavirdine and zidovudine: a European/Australian phase II trial.
The objective of the study was to investigate the safety and antiviral effect of three delavirdine dose regimens or placebo in combination with zidovudine in patients who were already taking zidovudine. Eighty-nine symptomatic HIV-1 seropositive individuals with CD4 cell counts between 50 and 350 cells/microl were included in this trial The influence of combination therapy on viral susceptibility to both zidovudine and delavirdine was investigated. Death or the occurrence, or re-occurrence of an AIDS-defining illness was considered as a clinical endpoint. The addition of delavirdine to the antiretroviral treatment regimen resulted in a significant, but transient, reduction in virus load, as determined by quantitative RNA measurements. CD4+ cell count did not change significantly. Susceptibility to zidovudine remained unchanged after 12 weeks of combination therapy, while 70% of the patients demonstrated a substantial decrease (> 10-fold) in sensitivity to delavirdine. Two patients suffered from an AIDS-defining disease during the study. No deaths occurred. Generally, the drug appeared to be safe. Skin rash was the most frequently observed adverse event (52%). In most patients the rash either resolved spontaneously or was treated successfully with a short course of antihistamines. The definite place of the compound in the management of HIV disease, in particular when given in combination with other antiretroviral agents, remains to be further explored.
Anti-HIV Agents↗
CD4 lymphocyte count as a predictor of the duration of highly active antiretroviral therapy-induced suppression of human immunodeficiency virus load.
The association between CD4 cell count and duration of virus load suppression was investigated in 558 patients in the Frankfurt HIV Clinic Cohort who had begun highly active antiretroviral therapy and who had virus load declines to </=500 copies/mL. The Kaplan-Meier method estimated viral rebound in 42.5% of patients by 24 weeks and in 64.3% by 84 weeks. Risk of viral rebound was independently associated with baseline and changes from baseline CD4 cell count. The achieved CD4 cell count was the most important factor for prediction of viral rebound (relative hazard, 5.4 for an updated CD4 cell count of <20 vs. >500 copies/mL; P=.0001). Baseline virus load was not associated with virus load rebound. Lower baseline CD4 cell counts were associated with increased risk of viral rebound; however, this risk was significantly reduced in persons with low baseline CD4 cell counts who experienced substantial increases in CD4 cell counts during follow-up.
Adult↗
A randomized, controlled trial of indinavir, zidovudine, and lamivudine in adults with advanced human immunodeficiency virus type 1 infection and prior antiretroviral therapy.
A randomized, double-blind, multicenter study of indinavir, zidovudine, and lamivudine was conducted in 320 adults with human immunodeficiency virus type 1 (HIV-1) infection, </=50 CD4 cells/mm3, and extensive prior zidovudine therapy. Patients received indinavir, 800 mg every 8 h; zidovudine, 200 mg every 8 h, and lamivudine, 150 mg twice daily; or all 3 drugs for 24 weeks. In an intention-to-treat analysis, proportions of patients with HIV-1 RNA <500 and <50 copies/mL, respectively, at week 24 were 56% and 45% in the indinavir-zidovudine-lamivudine group, 3% and 2% in the indinavir group, and 0% in the zidovudine-lamivudine group. Observed mean CD4 cell increases were 95, 78, and 6 cells/mm3 in the three-, one-, and two-drug arms, respectively. Regimens were generally well tolerated. Patients with advanced HIV-1 infection benefit from triple therapy with indinavir, zidovudine, and lamivudine, although the proportion with optimal response appeared to be lower in patients with low CD4 cell counts.
Acquired Immunodeficiency Syndrome↗
A family of insertion mutations between codons 67 and 70 of human immunodeficiency virus type 1 reverse transcriptase confer multinucleoside analog resistance.
To investigate the occurrence of multinucleoside analog resistance during therapy failure, we surveyed the drug susceptibilities and genotypes of nearly 900 human immunodeficiency virus type 1 (HIV-1) samples. For 302 of these, the 50% inhibitory concentrations of at least four of the approved nucleoside analogs had fourfold-or-greater increases. Genotypic analysis of the reverse transcriptase (RT)-coding regions from these samples revealed complex mutational patterns, including the previously recognized codon 151 multidrug resistance cluster. Surprisingly, high-level multinucleoside resistance was associated with a diverse family of amino acid insertions in addition to "conventional" point mutations. These insertions were found between RT codons 67 and 70 and were commonly 69Ser-(Ser-Ser) or 69Ser-(Ser-Gly). Treatment history information showed that a common factor for the development of these variants was AZT (3'-azido-3'-deoxythymidine, zidovudine) therapy in combination with 2',3'-dideoxyinosine or 2',3'-dideoxycytidine, although treatment patterns varied considerably. Site-directed mutagenesis studies confirmed that 69Ser-(Ser-Ser) in an AZT resistance mutational background conferred simultaneous resistance to multiple nucleoside analogs. The insertions are located in the "fingers" domain of RT. Modelling the 69Ser-(Ser-Ser) insertion into the RT structure demonstrated the profound direct effect that this change is likely to have in the nucleoside triphosphate binding site of the enzyme. Our data highlight the increasing problem of HIV-1 multidrug resistance and underline the importance of continued resistance surveillance with appropriate, sufficiently versatile genotyping technology and phenotypic drug susceptibility analysis.
Anti-HIV Agents↗
A prospective evaluation of the cost effectiveness of adding lamivudine to zidovudine-containing antiretroviral treatment regimens in HIV infection. European perspective.
BACKGROUND: A prospective cost-effectiveness analysis undertaken as part of the CAESAR (Canada, Australia, Europe, South Africa) placebo-controlled clinical trial showed that adding lamivudine to zidovudine-containing regimens for 1 year reduced progression to AIDS or death and, in addition, significantly reduced the number of hospitalisations, unscheduled outpatient visits and the requirement for medications for HIV-related illness. Data from all 1840 patients included in the intent-to-treat population of the CAESAR trial were used in the analysis reported in this paper. Because a third-party payer perspective was adopted, possible savings associated with increased productivity (indirect costs) were not taken into account. All costs were adjusted to 1997 prices. RESULTS: The savings associated with reduced healthcare resource use in the CAESAR study were estimated to be 3045 Deutschmarks (DM) [German analysis] or 432 pounds sterling (Pound) [UK analysis] per patient for the 1-year time period. These savings partly offset the cost of lamivudine in the 2 countries. The German analysis showed that the addition of lamivudine to zidovudine-containing regimens resulted in an incremental cost-effectiveness ratio of DM22,405 [95% confidence interval (CI): -DM2199 to DM59,154] for progression to AIDS/death avoided and of DM8869 (95% CI: -DM1047 to DM23,365) for HIV-related illness avoided. The corresponding ratios for the UK analysis were 12,030 Pounds (95% CI: 6752 Pounds to 21,888 Pounds) for progressions avoided and 4762 Pounds (95% CI: 2796 Pounds to 9484 Pounds) for new and recurrent HIV-related illness avoided. CONCLUSIONS: Our findings indicate that treatments that slow the progression of HIV infection to AIDS or death have the potential to facilitate healthcare savings during the period that the treatment is effective. The results also demonstrate that it is possible to undertake economic evaluations in parallel with a major clinical end-point study.
Adult↗
Update on study 006--EFV + AZT + 3TC versus the current 'standard of care' IDV + AZT + 3TC.
Study 006 is a pivotal Phase III, multicentre, randomized, open-label study designed to compare the antiretroviral activity and tolerability of efavirenz (EFV) + zidovudine (AZT) + lamivudine (3TC) with indinavir (IDV) + AZT + 3TC and EFV + IDV. Using both the 'observed data' analysis and intent-to-treat non-completer = failure analysis, the results at 48 weeks showed that efavirenz, in combination with AZT + 3TC was superior to IDV + AZT + 3TC. EFV + AZT + IDV was shown to be equally effective in patients with high and low baseline viral loads. Toxicities resulting in premature discontinuations were 3-fold higher in the IDV + AZT + 3TC arm than in both efavirenz-containing arms. Preliminary results suggested that efavirenz increased high density lipid (HDL) levels but the clinical significance of this observation is unknown. The results from Study 006 indicate that the combination EFV + AZT + 3TC is a highly active protease inhibitor-sparing regimen for first-line treatment of HIV-infected patients.
Acquired Immunodeficiency Syndrome↗
Coming therapies: abacavir.
Abacavir is a nucleoside analogue reverse transcriptase inhibitor (NRTI). It has a good oral availability and penetrates the CNS. The metabolism of abacavir is not dependent on cytochrome P450 thus avoiding significant drug-drug interactions. It has an antiviral potency comparable to that of protease inhibitors (PIs) or to dual nucleoside combinations. In addition, evidence has shown that it is effective in decreasing viral load and increasing CD4 count in HIV-infected patients, especially NRTI-naïve patients. Abacavir has an acceptable tolerability profile, although hypersensitivity reactions lead to discontinuation of therapy in approximately 3% of patients. Abacavir has a potential role in first- and second-line combination regimens and as part of a PI-sparing regimen.
Anti-HIV Agents↗