A pilot case-control study of zidovudine compared with zidovudine plus didanosine in patients with advanced HIV-1 disease and no previous experience with antiretrovirals

Although zidovudine (ZDV) is effective in HIV-1-infected patients, the duration of its efficacy may be short when treatment is started in advanced HIV disease. This pilot prospective case-control study was designed to evaluate the combination of ZDV plus didanosine [ddI] compared with ZDV monotherapy as an initial therapeutic strategy. 'Control' patients (ZDV monotherapy) were matched with 'case' patients (ZDV plus ddI combination therapy) according to the presence or absence of AIDS-defining criteria at entry and CD4 cell count. The case patient group consisted of 35 consecutive HIV-1-infected individuals with < or = 300 CD4 cells/mm3, no previous experience of antiretroviral therapy and who accepted treatment with a combination of ZDV plus ddI. The control patient group consisted of 35 consecutive patients with similar characteristics, but who preferred to start treatment with ZDV alone. Control patients received 250 mg ZDV bid and case patients received ZDV at the same dose plus ddI (200 mg bid). Primary study endpoints were virological (serum HIV-1 RNA) and immunological (CD4 cell count) responses. Viral phenotype (syncytium-inducing (SI) or non-syncytium-inducing (NSI)), development of mutations at codons 215, 41 and 74 and clinical progression (new AIDS-defining event or death) were also assessed. Virological and CD4 cell count responses were significantly greater and more sustained in the group treated with ZDV plus ddI than in the control group, with peak responses of -1.2 +/- 0.7 log10 versus -0.3 +/- 0.4 log10 at 1 month (P = 0.0003) and 61 +/- 52 cells/mm3 versus 19 +/- 25 cells/mm3 at 2 months (P = 0.001), respectively. In both groups the percentage of patients developing a mutation at codon 215 was around 80 per cent at 12 months. A mutation at codon 74 was detected in 30 per cent of case patients at 12 months. Five case patients (14 per cent) versus 12 control patients (34 per cent) showed signs of clinical progression (P = 0.09). In a multivariate model, clinical progression was significantly associated with a baseline     

HIV-1 viraemia changes in patients with and without syncytium-inducing phenotype treated with nucleoside analogues: a case-control study

Abstract. The objective of the present study was to investigate the effect of the nucleoside analogue treatment on serum viraemia, CD4+ cell count and disease progression in patients with and without syncytium-inducing (SI) HIV-I variants. To achieve this in a case-control study, 11 nucleoside-naive patients harbouring SI variants who started treatment with zidovudine or zidovudine plus didanosine were matched with 11 control patients who never formed SI variants during a follow-up of 48 weeks. The matching criteria were age, CD4+ cell count and CDC clinical category at the start of the study and exposure to the same antiretroviral treatment. During the follow-up there were no significant differences in the changes of serum HIV-I RNA viral load and CD4+ cell counts between the two groups. In contrast, AIDS or new AIDS-defining events were observed in five SI cases but in none of the non-SI controls ( P = 0.002). The emergence of a zidovudine-resistant mutation at codon 215 was observed in all the patients harbouring SI strains and in six of the subjects with non-SI variants ( P = 0.03). The results of the present study show that in patients carrying SI virus, measurements of CD4+ count or RNA viral burden are neither related to the virulence of the virus strains nor able to predict the clinical course of the disease, at least under antiretroviral drug conditions. Thus, determination of SI phenotype should be considered in the evaluation and monitoring of HIV-I therapies.     

Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial)

BACKGROUND: Once-daily combination therapy with emtricitabine, didanosine and efavirenz has been highly effective in clinical trials but its long-term efficacy and safety has not been previously reported. METHODS: This multicentre, single-arm, open-label trial enrolled 40 antiretroviral-naive HIV-1-infected patients who received a once-daily regimen of emtricitabine, didanosine and efavirenz. The objective was to assess the long-term effects of this combination on plasma HIV RNA levels, CD4+ T-cell counts, safety and tolerability. RESULTS: After 5 years, 73% and 68% of patients had plasma HIV RNA levels < 400 and < 50 copies/ml, respectively, in an intent-to-treat, missing-equals-failure analysis. Genotypic resistance on treatment emerged in six patients. There was a significant increase in CD4+ T-cell count of 294 x 10(6) cells/l. Only six patients discontinued study treatment, because of non-severe adverse events. Lipodystrophy was infrequent, and lipid and glucose profiles were favourable with a significant increase in high-density lipoprotein cholesterol. CONCLUSION: A convenient once-daily regimen of emtricitabine, didanosine and efavirenz provided durable antiretroviral response and was well tolerated through 5 years of therapy.     

Short-term anti-HIV activity of the combination of didanosine and hydroxyurea

The synergistic action of hydroxyurea with some other antiretroviral drugs led us to evaluate the effect of therapy with the combination of didanosine and hydroxyurea in HIV-1-infected patients. We aimed to assess the anti-HIV activity of therapy with this combination by measuring variations in viral load and in CD4 cell counts. We also evaluated the potential side effects of this drug combination in HIV-1-positive patients with advanced disease. A total of 15 HIV-1-seropositive homosexual men with a mean baseline CD4 cell count of 149 cells/mm3 (range: 1-430 cells/mm3) were recruited to the study, and received didanosine (200 mg) plus hydroxyurea (500 mg) twice daily for 12 weeks. Ten patients were didanosine naive and five had previously received didanosine (for > 3 months). The combination therapy was well tolerated, although grade 2-3 alopecia appeared in four patients who had very low CD4 cell counts (< 50 cells/mm3). No significant variation in renal, hepatic and pancreatic functions occurred. A significant reduction in the plasma HIV-1 RNA (> 0.5 logs) was observed in seven of ten patients naive to didanosine after weeks 4 and 12 of the study; five of these patients had a decrease in plasma HIV-1 RNA of > 1.5 logs, with two having a decrease of > 2.0 logs. The viral load became undetectable (below 200 copies/ml) in three patients. The patients whose plasma HIV-1 RNA levels were not significantly reduced by the combination therapy had a higher baseline viral load. CD4 cell counts did not increase significantly in most patients. We observed a better response in those patients who had virus of the non-syncytium-inducing phenotype. In conclusion, hydroxyurea in combination with didanosine was well tolerated and led to a reduction in viral load mainly in patients who were initially naive to didanosine.     

Time-dependence of survival predictions based on markers of HIV disease. Swiss HIV Cohort Study.

OBJECTIVE: To determine whether the ability of baseline clinical stage, viremia, and CD4 cell counts to predict mortality in HIV-1-infected patients changes with duration of follow-up. METHODS: Three hundred ninety-four patients were followed for an average of 29 months by the Swiss HIV Cohort Study, a practice-based registry of HIV-1-infected patients in Switzerland. Predictor variables were the baseline clinical stage, CD4 cell count, circulating HIV-1 RNA level, and the RNA/CD4 ratio; the outcome was death. The changes in relative risks of death over time were examined using survival models that extend the Cox model to allow for nonproportionality of hazards. RESULTS: During 949 person-years of follow-up, 169 patients died (mortality rate 17.8 per 100 person-years). Compared with clinical stage A, patients in stages B and C at baseline had much higher mortality rates in the subsequent year. The prognostic ability of stage C decayed over time (P = 0.03). By contrast, the relative risks associated with a 2-fold difference in CD4 counts remained remarkably stable, at approximately 0.6 (P = 0.81 for the time-dependence test). Relative hazards associated with a 10-fold difference in HIV RNA per milliliter and in HIV RNA per CD4 cell both tended to increase over time, but this trend failed to reach statistical significance (P = 0.21 and P = 0.08, respectively). CONCLUSIONS: Time-dependence patterns of prognostic ability varied widely among predictors, displaying gradual decay (clinical stage), stability (CD4 cells), and a trend to progressive increase (viremia). These results may affect clinical monitoring of HIV-infected patients and the interpretation of cohort studies of HIV-infected patients.     

Didanosine therapy in patients intolerant of or failing zidovudine therapy.

OBJECTIVE: To examine the effect of didanosine (2',3'-dideoxyinosine, ddI) on surrogate markers of HIV infection (CD4+ lymphocyte count, p24 antigen) and to evaluate the incidence of adverse effects from ddI. DESIGN: This study was performed as a retrospective chart review of patients who were enrolled in Bristol-Myers Squibb's expanded-access program for ddI. SETTING: Patient records were obtained from primary care physicians' offices. PATIENTS: Twenty-five HIV-infected patients diagnosed with AIDS or AIDS-related complex (ARC) who were intolerant of zidovudine (ZDV) therapy or deteriorating clinically despite ZDV therapy and were eligible for inclusion in the ddI expanded-access program. INTERVENTION: ddI was administered orally in a citrate-phosphate buffer every 12 hours. Patients were followed by their private physician on a monthly basis. MAIN OUTCOME MEASURES: Laboratory analysis at each month included CD4+ lymphocyte count, hemoglobin, hematocrit, serum amylase, uric acid, serum triglycerides, and p24 antigen. Mean CD4+ cell count, serum amylase, hemoglobin, and uric acid at each month during ddI therapy were compared with baseline concentrations for nine months. RESULTS: Patients had received prior ZDV therapy for an average of 15.5 months before starting ddI. Mean CD4+ cell counts increased from 53.9/mm3 at baseline to 72.4/mm3 after 4 months of therapy (p = 0.04) but returned to concentrations comparable with those at baseline after 5 months. One case of documented pancreatitis, two cases of suspected pancreatitis, and nine cases of peripheral neuropathy occurred during ddI therapy. The estimated mean cumulative dose for the development of neuropathy was 1.16 g/kg, which is lower than previously reported. CONCLUSIONS: Patients who have received prolonged therapy with ZDV or who have low initial CD4+ counts may not have sustained increases in CD4+ counts from ddI therapy. Also, development of peripheral neuropathy may occur at lower cumulative doses in these patient populations.     

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.     

Virological and immunological responses to a once-a-day antiretroviral regimen with didanosine, lamivudine and efavirenz

Current antiretroviral drugs cannot eradicate HIV infections, and persons living with HIV are often faced with very demanding daily therapeutic schedules that can induce poor adherence. More conveniently dosed and patient-friendly regimens are needed. We investigated, in this 48-week pilot study, a once-a-day highly active antiretroviral therapy regimen of didanosine, lamivudine and efavirenz. Seventy-five consecutive antiretroviral-naive subjects were enrolled. Over the 48-week period, plasma HIV-RNA levels declined sharply, with a median decrease at the end of the observation time >3.4 log copies/ml. The proportion of patients achieving a plasma HIV-RNA level below the limit of detection (50 copies/ml) was 77% (intention to treat analysis) at the end of the study period. The mean CD4 cell count increased steadily over time from 251 to 459 cells/microl. Antiviral efficacy was similar in patients with a baseline HIV-RNA level above or below 100,000 copies/ml. However, patients with a baseline CD4 cell count <200 cells/microl showed a significantly worse virological response than that observed in patients with higher baseline CD4 counts. Overall 15 patients interrupted therapy. In four cases treatment interruption was due to lack of treatment response; three additional patients were lost to follow-up or withdrew informed consent. Eight patients stopped therapy because of adverse events. The once-daily combination of didanosine, lamivudine and efavirenz resulted in sustained viral suppression and was well-accepted by patients. This regimen may offer advantages in selected difficult-to-treat populations, allows directly observed therapy and can be a safe and effective alternative in antiretroviral-naive patients. These encouraging pilot results need to be confirmed in a comparative clinical trial.     

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.     

Relation of peripheral neuropathy to HIV treatment in four randomized clinical trials including didanosine.

Peripheral neuropathy has been recognized as a dose-limiting adverse effect in Phase I studies of didanosine (ddI) therapy for HIV infection. To study the effect of the currently recommended lower dose of ddI, the databases of 4 randomized, controlled trials were used to assess the frequency of dose-limiting peripheral neuropathy during treatment with ddI 500 or 750 mg/d, compared with zidovudine (ZDV) monotherapy or combination therapy with ddI/ZDV or zalcitabine/ZDV. No between-group differences in risk factors for neuropathy (eg, infectious and metabolic factors, malignancy, concurrent medications) were observed in the individual trials, and the presence of these risk factors appeared to have no increased treatment effect on the occurrence of neuropathy. No significant between-group differences were observed in the individual studies with regard to the incidence or time to onset of peripheral neuropathy. Analysis of the combined results by treatment regimen showed no significant difference in the incidence of neuropathy between recipients of ddI 500 mg/d, ddI 750 mg/d, or ZDV and no significant difference in the cumulative dose received until the onset of neuropathy between the ddI 500- and 750-mg regimens. Entry CD4+ cell counts were significantly predictive of neuropathy, with each 100-cell/microL decrement associated with a 17% increase in risk (P = 0.002); a CD4+ cell count of <50 cells/microL was highly predictive of neuropathy (P = 0.0001). In summary, the risk for peripheral neuropathy was not increased by treatment with ddI versus comparator regimens or by treatment with ddI at the dosages used in studies conducted more recently than the Phase I trials. Peripheral neuropathy seems more likely to be associated with advanced HIV infection and lower CD4+ cell counts (particularly counts <50 cells/microL) than with ddI therapy at the currently recommended dose.     

Didanosine plus stavudine with or without hydroxyurea in HIV-1-infected patients: 1 year follow-up. Swiss HIV Cohort Study

A total of 144 human immunodeficiency virus (HIV)-infected patients (mean CD4 cell count, 367 cells/mm3) were included in a double-blind placebo-controlled trial testing the efficacy on surrogate markers of HIV progression of the combination didanosine (2',3'-dideoxyinosine or DDI) plus stavudine (2',3'-didehydro-2',3'-dideoxythymidine or D4T) with or without hydroxyurea. The primary end point was a reduction of HIV RNA levels to below 200 copies/ml after 12 weeks of treatment. The results showed that the triple combination was associated with a more profound decrease in HIV RNA with an increased proportion of patients with viraemia < 200 copies/ml. This effect persisted for the majority of the patients after a 48 week follow-up. In contrast, the increase in CD4 cell counts was less in patients treated with hydroxyurea because of lymphopenia, and adverse events were more frequent in hydroxyurea-treated patients. In conclusion, the addition of hydroxyurea consistently improved the antiviral activity of the didanosine/stavudine combination over a 48 week follow-up. Increased toxicity and decreased effect on CD4 cell counts might inspire caution.     

Demographics of HIV survival revisited

HIV mortality among blacks, women, and injection drug users is disproportionately high in comparison to other HIV-infected populations. It has been noted that differential survival may be related to access to care. A team at Johns Hopkins followed 1,372 patients at a single urban HIV clinic over 1.6 years. During this time, 427 patients died. After adjusting for CD4 counts, there was not a significant difference in survival between men and women, blacks and whites, injection drug users and non-users, and people with annual incomes above and below $5,000. Predictors of mortality included initial CD4 counts below 350 cells/mm3, prior antiretroviral therapy, and older age; and indicators of survival included employment at enrollment, antiretroviral therapy after enrollment, and PCP prophylaxis. These findings indicate that access to care needs to be improved, since demographic differences in survival disappear when care and other factors are held constant.     

Meta-analysis of five randomized controlled trials comparing continuation of zidovudine versus switching to didanosine in HIV-infected individuals

A meta-analysis of the original data from 2411 patients in the ACTG 116A, ACTG116B/117, ACTG175, BMS010 and CTN002 trials was conducted to improve the estimate of the effect of switching from zidovudine to didanosine on rates of clinical progression, to better quantify the rates of neurological events (including AIDS dementia and peripheral neuropathy) and to examine the effects of switching from zidovudine to didanosine among women and racial subgroups. In total, 1012 patients received zidovudine therapy, 557 received high-dose didanosine and 842 received didanosine. The median duration of follow-up was 15 months. Ninety-one percent of patients were male, 78% were white, mean age was 36.5 years. The median CD4 count was 195 cells/mm3 (range: 0-762) and the median duration of prior zidovudine therapy was 14 months (range: 0.1-94). There were 336 deaths and 686 new AIDS-defining illnesses (ADIs) or deaths. After stratification by study and adjusting for baseline CD4 count and presence of an AIDS diagnosis prior to baseline, the relative risks of death associated with switching from zidovudine to high-dose didanosine or to didanosine were 0.94 (P = 0.64) and 0.77 (P = 0.07), respectively. The relative risks of a new ADI or death associated with switching from zidovudine to high-dose didanosine and didanosine were 0.78 (P = 0.01) and 0.66 (P = 0.0001), respectively. There were 21 documented cases of AIDS dementia complex (ADC) during the entire follow-up period. The rates per 100 person years of follow-up were 0.70, 0.65 and 0.41 for the zidovudine, high-dose didanosine and didanosine arms, respectively. There were no significant differences in risks of ADC between treatment arms (zidovudine versus high-dose didanosine: P = 0.30, zidovudine versus didanosine: P = 0.97, didanosine versus high-dose didanosine: P = 0.41). Our data confirm a clinical benefit and CD4 increase associated with a switch from zidovudine to didanosine therapy. No statistical differences were detected between doses of didanosine with respect to survival or progression to a new ADI or death. Furthermore, there was no statistical difference in the frequency of ADC between treatment arms.     

Effects of subcutaneous interleukin-2 therapy on CD4 subsets and in vitro cytokine production in HIV+ subjects.

HIV infection is characterized by the reduction of the CD4+, CD45RA+, CD26+, and CD28+ lymphocyte subsets and of the in vitro production of IL-2, IL-4, and interferon-gamma; on the contrary, chemokine production is usually increased. These abnormalities are only partially restored by antiretroviral chemotherapy. Therapy with interleukin-2 has been proposed to restore the functions of the immune system, but the mechanisms by which IL-2 exerts its activities are unknown. The aim of this study was to define the effects of rIL-2 administration on CD4+, CD45RA+, CD45R0+, and CD26+ lymphocytes and on the in vitro production of IL-2, IL-4, IL-10, IFN-gamma, RANTES, and sCD30 in HIV+ patients. 10 HIV+ patients with CD4 cell counts between 200 and 500 cells/mm3 were treated with six cycles of subcutaneous recombinant IL-2 administration, in combination with zidovudine and didanosine. This therapeutic regimen resulted in a remarkable increase in the number of CD4+ cells and in the prolonged reduction of the levels of viremia. CD45R01 cells were expanded during the first cycle of therapy, while CD45RA+/CD26+ cells predominated after the third cycle. At this time, the in vitro production of IL-2, IL-4, IFN-gamma, and sCD30 were significantly upregulated. These results demonstrate that rIL-2 in HIV+ patients induces the reconstitution of the CD4/CD45RA lymphocytes subtype. This expanded cell population recovered the ability to produce in vitro IL-2, IL-4, and IFN-gamma. These effects may be beneficial to HIV+ patients by improving their immune response to microorganisms or vaccines.     

Acyclovir in combination with zidovudine does not prolong survival in advanced HIV disease

The aim of this study was to evaluate the association between acyclovir use and survival in HIV-infected patients. To achieve this, we used survival analysis in an observational cohort of HIV-infected patients enrolled in primary care at an urban HIV clinic. We measured survival in a cohort of HIV-infected patients who had CD4 cell counts < or = 500/mm3 and who enrolled for care at a single urban HIV clinic between December 1988 and April 1995. We compared survival in users of acyclovir alone, zidovudine alone, and acyclovir and zidovudine in combination with the survival of those using neither drug. Factors associated with improved survival were identified using Cox proportional hazards analysis. Among the 1408 patients enrolled, there were no significant differences in overall survival between acyclovir users and non-users. After adjustment for CD4 cell count, the use of other antiretroviral agents, race, transmission risk and a history of herpesvirus infection, acyclovir use alone was independently associated with a relative hazard (RH) of death of 1.008 (P = 0.969); zidovudine use alone with a RH of 0.559 (P < 0.001); and combination use of acyclovir and zidovudine associated with a RH of 1.062 (P = 0.788). Therefore we conclude that the use of acyclovir is not associated with prolonged survival in this cohort of HIV-infected patients.