Immunological and virological activity of zalcitabine and zidovudine in combination in HIV-positive people with CD4 cell counts of between 200-500 cells/mm3

We evaluated the effect of combination therapy with zidovudine (AZT) plus zalcitabine (ddC) in human immunodeficiency virus type 1 (HIV-1)-infected patients who had not previously received antiretroviral treatment ('naive' patients). The immunological and virological parameters evaluated were CD4 cell count, syncytium-inducing (SI) viral phenotype and plasma HIV-1 RNA copies/ml (HIV viral load). A total of 75 patients entered the study, with CD4 cell counts between 200 and 500 cells/mm3. All received zidovudine (200 mg) plus zalcitabine (0.75 mg) three times daily for 24 weeks. Treatment was well tolerated. However, four patients presented with anaemia (haemoglobin < 10.0 g/dl) and one patient had both anaemia and neutropenia (0.8 x 10(9) neutrophils/l). Combination therapy with zidovudine plus zalcitabine resulted in a pronounced improvement of virological and immunological markers. Approximately 25% of patients achieved undetectable plasma HIV RNA levels (< 200 copies/ml) at week 24. At the end of the study (24 weeks) a significant reduction (> 0.5 log) of plasma HIV RNA was observed in approximately 70% of patients and in 50% an even greater decrease (> 1 log) was achieved. The most significant decrease in mean plasma HIV RNA levels was observed at week 4, whereas the highest increase in CD4 cell count was found at week 24. Approximately 80% of patients who showed baseline plasma HIV RNA levels below 20000 copies/ml had less than 5000 copies/ml at week 24. The plasma HIV RNA reduction observed at week 4 was significantly maintained at week 24. Therefore, we can rapidly select those who will not respond to therapy and adjust the treatment after a short interval. Our study supports the idea of early therapy because all patients who reached undetectable levels of plasma HIV RNA at week 24 had at baseline a median plasma HIV RNA load of 2560 copies/ml. In conclusion, zidovudine in combination with zalcitabine was well tolerated in the majority of patients and led to a significant reduction in plasma HIV RNA copies in most of the patients with initial viraemia lower than 20000 copies/ml.     

Stavudine plus didanosine and nevirapine in antiretroviral-naive HIV-infected adults: preliminary safety and efficacy results. VIRGO Study Team

The objective of this open-label trial is to evaluate the virological and immunological effects of triple therapy with stavudine (40 mg twice daily if > or = 60 kg, 30 mg twice daily if < 60 kg)/didanosine (400 mg once daily if > or = 60 kg, 300 mg once daily if < 60 kg)/nevirapine (200 mg daily from day 1 to 14, then 200 mg twice daily) in 60 antiretroviral-naive HIV-infected adults with CD4 cell counts > or = 200 cells/mm3 and plasma HIV RNA > or = 5000 copies/ml. At present, 59 patients have begun receiving the trial regimen. Characteristics of patients at baseline were as follows: 46 men/13 women, CDC stage A, 75%; mean CD4 cell count, 429 cells/mm3; mean HIV RNA, 4.6 log10 copies/ml). Mean decrease of viral load was -1.9 log10 at week 4 (n = 39), -1.9 log10 at week 16 (n = 20), with HIV RNA below the detectable level (< 500 copies/ml) in 62% of patients at week 4 and 85% at week 16. Mean CD4 cell count increase was +118 cells/mm3 at week 4. Cutaneous intolerance occurred within the first 4 weeks in 11/59 (19%) patients after a mean of 14 days (range, 3-24 days) and led to nevirapine discontinuation in 3/11 patients. Preliminary results of this ongoing trial show that combination therapy with stavudine/didanosine/nevirapine is a convenient (seven pills in two daily intakes) triple-therapy regimen with rapid immunological and antiviral effects. Rash, frequent in the first weeks of therapy, usually can be managed without stopping nevirapine. Long-term suppression of plasma HIV RNA with this combination needs to be confirmed but may support use of nevirapine as a component of first-line anti-HIV therapy along with two nucleosides.     

AVANTI 3: a randomized, double-blind trial to compare the efficacy and safety of lamivudine plus zidovudine versus lamivudine plus zidovudine plus nelfinavir in HIV-1-infected antiretroviral-naive patients

The objective of our randomized, multicentre, double-blind, placebo-controlled study was to investigate the safety, tolerability, and antiretroviral and immunological effect of double and triple combination therapy regimens. A total of 105 antiretroviral therapy-naive patients were randomized to receive either zidovudine (300 mg twice per day) plus lamivudine (150 mg twice per day) plus nelfinavir placebo (three times per day) (n=52), or zidovudine/lamivudine (dose as before) plus nelfinavir (750 mg three times per day) (n=53) for 28 weeks. After this time, patients were allowed to switch to open-label zidovudine/lamivudine/nelfinavir. The overall log10 reduction from baseline in plasma HIV-1 RNA was significantly greater in the zidovudine/lamivudine/nelfinavir group than the zidovudine/lamivudine group (P=0.001; median treatment difference, -1.01 log10 copies/ml; 95% confidence interval -1.23 to -0.79), as measured by the average area under the curve minus baseline over 28 weeks. Increases from baseline in CD4 cell counts were statistically significantly greater in the zidovudine/ lamivudine/nelfinavir group (101.5 cells/ml) than the zidovudine/lamivudine group (47.0 cells/ml; P=0.027) at week 28. Of note, the addition of nelfinavir from weeks 28-52 led to an increase in the proportion of subjects with plasma HIV-1 RNA <400 copies/ml from 17% (9/52 patients on zidovudine/lamivudine) to 50% (13/26 patients who switched to zidovudine/lamivudine/nelfinavir). Incidence of drug-related adverse events was similar in the two groups, except for nausea (more common in zidovudine/lamivudine group; 40 versus 17%) and diarrhoea (more common in zidovudine/lamivudine/nelfinavir group; 45 versus 14%). In conclusion, our study confirms the efficacy of triple combination therapy with two nucleoside analogues and a protease inhibitor compared with double-nucleoside therapy. Interestingly, the addition of nelfinavir to zidovudine/lamivudine, even after 6 months of double nucleoside therapy, led to a substantial virological benefit that was sustained over 24weeks in a subset of patients.     

Efficacy and safety of once-daily combination therapy with didanosine, lamivudine and nevirapine in antiretroviral-naive HIV-infected patients

BACKGROUND: Simplified antiretroviral regimens are needed to improve patient adherence and quality of life. The purpose of this study was to evaluate the efficacy and safety of a once-daily regimen consisting of didanosine (ddI), lamivudine (3TC) and nevirapine (NVP) for adult antiretroviral-naive patients with HIV-1 infection. METHODS: This was a prospective, one-arm, multicentre pilot study. Daily drug dosage was 250 or 400 mg didanosine, 300mg lamivudine and 400 mg nevirapine. The primary outcome measure was the percentage of patients with a plasma HIV-RNA level <50 copies/ml at 12 months on an intention-to-treat (ITT) basis. RESULTS: Seventy patients were enrolled in the study. At baseline, mean plasma HIV-1 RNA was 5.10log10 copies/ml, and mean CD4 cell count was 262 cells/microl. At month 12, 67% (95% CI: 56-78) of patients maintained a viral load of <50 copies/ml in the ITT analysis and CD4 counts increased a median of 201 cells/microl. The treatment was more effective in patients with baseline CD4 counts >100 cells/microl than in those with a poorer immunological status at baseline, although the number of patients with CD4 counts <100 was low. Four patients died during the study period. Therapy was discontinued in 18 patients due to virological failure in 11, adverse events in seven, loss to follow-up or withdrawal of consent in four and death in one. Eight out of nine patients with available genotype after virological failure showed resistance mutations to NVP (Y181C and others) and 3TC (M184V/I), and four of them also had ddI resistance (L74V). The lipid profile was favourable, with a decrease in the ratio of total-to-high density lipoprotein cholesterol. CONCLUSION: A once-daily combination of ddI, 3TC and NVP seems to be an effective, safe and easy-to-take regimen in antiretroviral-naive patients, at least in those who do not have severe immunodepression at baseline.     

An open-label trial of stavudine, lamivudine and efavirenz in the treatment of HIV-positive, treatment-naive patients, and implications for clinical practice

A phase II, open-label study of stavudine, lamivudine and efavirenz resulted in significant reductions in plasma HIV-1 RNA over a 24 week period in human immunodeficiency virus (HIV)-infected individuals. The trial currently has 68 patients, and this presentation covers data on the first 42 patients enrolled for 24 weeks. The mean plasma HIV-1 RNA on entry was 75858 HIV RNA copies/ml, and the mean CD4 count was 380 cells/mm3. After 24 weeks, the CD4 count increased by 169 cells/mm3 above baseline. plasma HIV-1 RNA was markedly reduced: at 24 weeks, more than 97% of patients had <50 HIV RNA copies/ml based on observed data, and 89% of patients had <50 copies/ml based on strict intent-to-treat analysis (non-completer=failure). The favourable interactions of these agents resulted in no discontinuations owing to adverse effects. This regimen provides an important first-line treatment for antiretroviral-naive patients.     

Results of the ALBI trial: a randomized comparison of stavudine/didanosine, zidovudine/lamivudine and alternating treatment in antiretroviral-naive patients

In the ALBI trial, 151 antiretroviral-naive patients with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels of 10,000 to 100,000 copies/ml and CD4 cell counts > or = 200 cells/mm3 received 24 weeks of treatment with stavudine/didanosine (n=51), zidovudine/lamivudine (n=51) or stavudine/didanosine for 12 weeks followed by zidovudine/lamivudine (n=49). Baseline plasma HIV-1 RNA and CD4 cell counts were comparable in the treatment groups. The mean decrease in plasma HIV-1 RNA at 24 weeks in the stavudine/didanosine group (2.26 log10) was significantly greater than that in either the zidovudine/lamivudine group (1.26 log10) or the alternating treatment group (1.58 log10) (P<0.0001 for both). Proportions of patients with plasma HIV-1 RNA level <500 copies/ml (91% vs 42% and 60%) and <50 copies/ml (47% versus 4% and 9%) were significantly greater in the stavudine/didanosine group (P<0.001 for pairwise comparisons). Stavudine/didanosine was associated with a mean increase in CD4 cell count (124 cells/mm3) significantly greater than that in the zidovudine/lamivudine group (62 cells/mm3, P<0.01) and comparable to that in the alternating group (118 cells/mm3). All study regimens were well tolerated. These findings, indicating superiority of stavudine/didanosine over zidovudine/lamivudine in virological and immunological response over 24 weeks, suggest that the combination should be considered as a basis for highly active antiretroviral therapy.     

Esophageal ulcer caused by cytomegalovirus: resolution during combination antiretroviral therapy for acquired immunodeficiency syndrome

A 36-year-old man with a 5-year history of untreated human immunodeficiency virus (HIV) infection had odynophagia for 14 days. Fifteen days earlier, he had begun taking trimethoprim-sulphamethoxazole and combination antiretroviral therapy that included lamivudine, zidovudine, and nelfinavir. He had no history of opportunistic infection. The CD4 lymphocyte count was 67/microL and HIV-RNA level was 359,396 copies/mL. Esophagogastroduodenoscopy revealed a large, well-circumscribed esophageal ulceration 31 cm from the incisors. Histopathologic examination of esophageal biopsy specimens showed cytopathic changes diagnostic of cytomegalovirus (CMV). In situ DNA hybridization was positive for CMV. While combination antiretroviral therapy was continued, the esophageal symptoms resolved within 4 days of endoscopy without specific therapy for CMV. Follow-up endoscopy 4 weeks later revealed a normal-appearing esophagus, and the patient has remained symptom-free for 10 months.     

Pharmacokinetics and pharmacodynamics of efavirenz and nelfinavir in HIV-infected children participating in an area-under-the-curve controlled trial

Fifty human immunodeficiency virus (HIV)-infected children participated in an area-under-the plasma concentration-time curve (AUC)-controlled trial of efavirenz and nelfinavir. Pharmacokinetic evaluations were performed at weeks 2, 6, and 56. Efavirenz and nelfinavir doses were adjusted to achieve AUC values of 60-120 and > or = 10 mg h/l, respectively. Thirty-seven (74%) children met the efavirenz target and 41 (82%) the nelfinavir by week 10. Children with AUC values for both drugs above the first quartile were more likely to reach < 400 copies/ml of HIV RNA at week 8. Efavirenz and nelfinavir oral clearance increased 37 and 62% from weeks 2 to 56, respectively, in 34 children who continued on therapy at week 56. AUC values at week 56 were not different between children who did or did not have HIV RNA < 400 copies/ml. Dose adjustment to achieve specific AUC values in these children reduced the risk of suboptimal exposure and achieved high rates of virologic suppression.     

Determination of HIV RNA concentration for evaluation of the efficacy of combined therapy of HIV infection

Plasma HIV RNA (viral load) and count of CD4+ T cells were evaluated in 23 patients with HIV infection treated with invirase (1800 mg/day), zidovudine (600 mg/day), and zalcitabine (2.25 mg/day) for 6 months in order to evaluate the efficiency of antiretroviral therapy. Viral load was measured by AMPLICOR HIV-1 Monitor test. The reproducibility of HIV RNA measurements was in line with reported data (CV 15-41%), allowing highly accurate (15%) evaluation of RNA in a standard control sample provided by National Institute for Biological Standards and Control, Great Britain. Plasma HIV RNA concentration decreased to an undetectable level (below 400 RNA copies/ml plasma) after 6 months of treatment in 52.2% patients. In 17.4% the therapy failed, and in 30.4% it resulted in a reduction of viral load to > 1 lg, although HIV RNA was still detected in the plasma after 6-month therapy. The count of CD4+ T cells increased by 9.5%. Changes in the viral load outstripped changes in CD4+ cells. Viral load was in high correlation with the count of CD4+ lymphocytes: -0.53, p = 0.01 before treatment and -0.61, p = 0.002 after 6-month treatment.     

Evaluation of hiv p24 antigen,beta2-microglobulin,neopterin, soluble cd4, soluble cd8, and soluble interleukin-2 receptor levels in patients with aids or aids-related complex treated with 2′,3′-dideoxyinosine (ddl)

Circulating HIV P24 antigen, beta2-microglobulin, neopterin, soluble CD4, soluble CD8, and soluble interleukin-2 receptor were measured in 13 zidovudine-intolerant patients (8 with ARC and 5 with AIDS) treated with dideoxyinosine (ddI). Measurements were made at baseline and at several intervals during therapy. Mean levels of HIV P24 antigen decreased early and significantly (^P<0.01) after 2 weeks of ddI administration and remained low at weeks 8 and 12. In addition, mean SCD8 levels decreased late and significantly (^P<0.02) after 16 weeks of ddI treatment and remained low at 24 weeks. In contrast, ddI administration had no substantial effect on mean levels of beta2-microglobulin, neopterin, soluble CD4, and soluble interleukin-2 receptor. ddI administration appears to have been associated with early reduction of HIV P24 antigen levels and later reduction of SCD8 mean levels in these patients.     

Effect of weekly adefovir (PMEA) infusions on HIV-1 virus load: results of a phase I/II study

The compound 9-(2-phosphonylmethoxyethyl)adenine (adefovir; PMEA) is a potent inhibitor of a number of viruses in vitro, such as human immunodeficiency virus (HIV) type 1 and 2, herpes simplex virus (HSV) type 1 and 2, human papillomavirus virus (HBV) and Epstein-Barr virus (EBV). Adefovir also proved to be effective in vivo against feline immunodeficiency virus (FIV) in cats and simian immunodeficiency virus (SIV) in rhesus monkeys. In an open, non-placebo-controlled trial the antiviral activity of weekly doses of adefovir in nine patients with AIDS or AIDS-related complex was studied for a period of 11 weeks. CD4 cell counts at baseline were between 10 and 450 cells/mm3, HIV-1 RNA levels at baseline were between 24,210 copies/ml and 406,197 copies/ml. The drug was administered intravenously at a dose of 1000 mg every week and plasma viral load was assessed at multiple points during the study. Administration of adefovir was tolerated well and no severe side effects were seen. The response to adefovir treatment differed widely between patients. The increase in CD4 cell count at end point ranged from -40 to 120 cell/mm3. The lowest HIV RNA levels were measured after 3-5 days, showing an increase thereafter. The nadir in viral load was achieved after 2 weeks, with a mean viral load decline of 0.7 from baseline. The decrease of the HIV RNA level at end point ranged from -0.3 log10 to 1.8 log10 with a mean decrease of 0.4 log10. Our results indicate that adefovir given intravenously once weekly has a short-lasting initial antiviral effect. The effect of more frequent dosing requires further evaluation. If adefovir is to be useful clinically, it needs to be combined with other antiviral agents.     

Relationship between CD4 count, viral burden, and quality of life over time in HIV-1-infected patients

BACKGROUND: Although surrogate markers such as CD4 counts and viral burden (HIV-1 RNA) are predictive of AIDS-related disease progression, little is known about the relationship between changes in surrogate markers and health-related quality of life (HRQOL) outcomes. This study investigated how changes in CD4/mm3 and viral burden (RNA copies/mL) are related to changes in HRQOL as indexed by the Medical Outcomes Study HIV Health Survey (MOS-HIV-30). METHODS: Subjects were HIV-1-infected patients with CD4 counts <300/mm3 enrolled in a double-blind, randomized clinical trial of delavirdine. As part of the clinical protocol, patients completed the MOS-HIV-30, from which the Physical Health (PHS) and Mental Health (MHS) summary scores were used for analyses. HRQOL and surrogate marker data assessed up to 2 years after randomization were analyzed for a total of 1,112 patients. RESULTS: Individual patients' initial status (intercepts) and rates of change (slopes) over time for log CD4, log RNA, PHS, and MHS were estimated with the use of empirical Bayes. Early response to treatment correlated with HRQOL better for RNA than for CD4. However, the relationship between weekly change and HRQOL was stronger for CD4 than for RNA. CONCLUSIONS: Surrogate markers are significantly associated with HRQOL outcomes. Improvements in HRQOL over time are associated with lower initial viral load and with increases in CD4 counts. Limitations concerning the restricted variability of the change scores are addressed.