Virologic and immunologic values allowing safe deferral of antiretroviral therapy

OBJECTIVE: To determine how long highly active antiretroviral therapy can be deferred in HIV-1 infected persons. DESIGN: Observational cohort study of HIV-1 infected men at four academic centers in the USA. OUTCOME: Progression to clinical AIDS or to CD4 cell counts < 200 x 10(6)/l in the absence of antiretroviral therapy among HIV-1 infected men. RESULTS: No participant with a CD4 cell count between 201 x 10(6) and 350 x 10(6)/l and having < 20 000 copies/ml of HIV RNA progressed to clinical AIDS within 1 year. In men with > 350 x 10(6) CD4 cells/l and < 60 000 copies of HIV RNA/ml there were also no instances of progression to clinical AIDS within 1 year. No participant with < 10 000 copies HIV RNA/ml and between 201 x 10(6) and 350 x 10(6) CD4 cells/l had a decrease in CD4 cells to < 200 x 10(6)/l within 1 year. In men with baseline CD4 cell counts > 350 x 10(6)/l and HIV RNA < 30 000 copies/ml, only 3% had a decrease in CD4 cell count to < 200 x 10(6)/l within 1 year. CONCLUSION: This analysis supports recommendations to defer therapy in HIV-1 infected individuals with CD4 cell counts > 350 x 10(6)/l and HIV RNA < 60 000 copies/ml and in persons with CD4 cell counts between 201 x 10(6) and 350 x 10(6)/l and < 20 000 copies/ml HIV RNA. Up to 79% of persons with > 350 x 10(6) CD4 cells/l and 29% with CD4 cell counts between 201 x 10(6) and 350 x 10(6)/l may, with close monitoring, safely defer therapy.     

Long-term immunological response in HIV-1-infected subjects receiving potent antiretroviral therapy

OBJECTIVE: To determine the long-term T-lymphocyte response to highly active antiretroviral therapy (HAART) and to define predictors of the immunological response. DESIGN: Cohort study, including 135 HIV-1-infected subjects at a city general practice who commenced HAART between 1996 and 1998. METHODS: Collection of plasma HIV-1 RNA, CD4+ and CD8+ T-lymphocyte data at 3-6 monthly time intervals over 2 years. RESULTS: Seventy-three subjects (54%) achieved suppression of plasma HIV-1 RNA to levels below 400 copies/ml during the observation period, 31 individuals (23%) had detectable plasma HIV-1 RNA below 10,000 copies/ml and 31 subjects (23%) had virological failures with viral loads above 10,000 copies/mL. Median CD4+ T lymphocytes increased from 246 to 463 x 10(6) cells/l, showing a median rise of 20 x 10(6) cells/l per month in the first 3 months and 7 x 10(6) cells/l per month thereafter. The proportion of individuals who reached CD4+ cell counts above 500 x 10(6) cells/l increased from 8% at baseline to 54% at 2 years. Treatment-na?ve individuals, subjects with a large reduction of HIV-1 RNA or a large early CD8+ increase had better early CD4+ responses. Long-term CD4+ T-cell increases were inversely correlated with mean plasma HIV-1 RNA levels. Baseline CD4+ T-cell count was the most important determinant of reaching CD4+ cell counts above 500 x 10(6) cells/l. Nineteen per cent of subjects had no further CD4+ T-cell increases in the second year of therapy despite undetectable viral load. CONCLUSIONS: Immune reconstitution is a slow process, showing a large individual variability. The virological response to HAART was the most important determinant of the immunological short- and long-term response.     

Plasma cytomegalovirus DNA, pp65 antigenaemia and a low CD4 cell count remain risk factors for cytomegalovirus disease in patients receiving highly active antiretroviral therapy

OBJECTIVE: To study the natural history and the current risk factors for cytomegalovirus (CMV) disease in the context of highly active antiretroviral therapy (HAART). SETTING: Prospective multicentre cohort in 15 university hospitals in France. METHODS: A group of 198 patients with CD4 cell count < 100 x 10(6) cells/l (or < 200 x 10(6) cells/l under HAART for at least 2 months), no previous CMV disease and CMV-positive serology were followed every 4 months clinically and for virological testing including HIV RNA and CMV blood markers (culture, pp65 antigenaemia, plasma CMV DNA and CMV late mRNA by the polymerase chain reaction). RESULTS: At inclusion, median CD4 was 77 x 10(6) cells/l (0-308) and 85% of the patients received protease inhibitors. The percentage of patients receiving HAART reached 99% at 12 months. After a follow-up of 23.6 months, the incidence of CMV disease was 3.2/100 patient-years [95% confidence interval (CI) 1.3-5.0]. In univariate Cox models, all the CMV markers, a CD4 cell count remaining < 75 x 10(6) cells/l and an HIV viral load > 100,000 copies/ml were predictive for CMV disease. The hazard ratios for CMV disease were 11 for blood culture; 14 and 70 for pp65 antigenaemia of > or = 1 and > or = 100 nuclei/200,000 cells, respectively; 35 for plasma CMV DNA; 6 for CMV mRNA; 29 for CD4 < 75 x 10(6) cells/l; and 12 for HIV RNA > 100,000 copies/ml. In a stepwise multivariate analysis, only three covariates were independently associated with the occurrence of a disease: plasma CMV DNA, pp65 antigenaemia > or = 100 nuclei/200,000 cells and a CD4 count < 75 x 10(6) cells/l. CONCLUSION: CMV blood markers and CD4 count < 75 x 10(6) cells/l remain risk factors for CMV disease in patients receiving HAART. Analysis of plasma CMV DNA by the polymerase chain reaction is a reproducible and standardized tool that could be used as a decision marker for initiating CMV pre-emptive therapy.     

Absolute count and percentage of CD4+ lymphocytes are independent predictors of disease progression in HIV-infected persons initiating highly active antiretroviral therapy

BACKGROUND: Highly active antiretroviral therapy (HAART) is recommended when the absolute CD4(+) T lymphocyte count is <200 cells/mm(3), and it should be considered when that count is > or =200, although the optimal timing when it is > or =200 is unclear. Because preliminary data had suggested that a low CD4(+) T lymphocyte percentage (%CD4) is associated with disease progression in persons initiating HAART who have a higher absolute CD4, we sought to further characterize the predictive utility of %CD4. METHODS: We conducted an observational study of persons in Collaborations in HIV Outcomes Research/US cohort who initiated their first HAART regimen between 1997 and 2004, received > or =30 days of therapy, and had baseline values of absolute CD4, %CD4, and HIV-1 RNA. Cox proportional-hazards models determined associations between %CD4 and disease progression (to either a new AIDS-defining event [ADE] or death). RESULTS: Of 1891 persons, 11% were female and 18% were African American; the median age was 38 years. Median follow-up was 55 months (interquartile range, 23-83 months), and 468 (25%) had disease progression. Multivariable analysis including age, race, sex, HIV-1 RNA, prior antiretroviral therapy, probable route of infection, prior ADE, absolute CD4, and %CD4 was performed; prior ART (P<.0001), injection-drug use (P=.04), lower absolute CD4 (P=.002), and lower %CD4 (P=.002) predicted disease progression. CONCLUSIONS: %CD4 at initiation of the first HAART regimen predicted disease progression independent of absolute CD4; %CD4 may be used to determine the timing of HAART.     

Effect of highly active antiretroviral therapy on cervicovaginal HIV-1 RNA

OBJECTIVES: To determine the frequency of cervicovaginal lavage and plasma HIV-1 RNA levels that are below detectable levels (< 400 copies/ml) among women on highly active antiretroviral therapy (HAART), non-HAART and on no therapy. To compare the effect of initiating HAART on the timing of HIV-1 RNA suppression in the blood plasma and genital tract among antiretroviral-na?ve women. METHODS: Data were obtained from 205 HIV-infected women with paired plasma and cervicovaginal lavage viral load measurements. Seven antiretroviral-na?ve women starting HAART had viral load measurements performed daily for one week, at 2 weeks and at 1 month after initiating therapy. Viral load quantification was carried out by nucleic acid sequence-based amplification assay. The lower limit of detection was 400 copies/ml. RESULTS: Plasma and cervicovaginal HIV-1 RNA was detectable in 71 and 26% of the women, respectively. Among women with plasma viral loads less than 400, 400-9999, and 10,000 copies/ml or over, genital tract HIV-1 RNA was detected in 3, 17 and 48%, respectively (P < 0.001). Fifty-one per cent of the women with CD4 cell counts of less than 200/mm3 had detectable cervicovaginal viral loads compared with 18% among women with CD4 cell counts of 200/mm3 or over (P < 0.001). Cervicovaginal HIV-1 RNA was less than 400 copies/ml in 85% of those on HAART, 69% of those on non-HAART and 69% of those on no therapy (P < 0.045). In seven antiretroviral-na?ve women initiating HAART, cervicovaginal HIV-1 RNA decreased by 0.7-2.1 log10 within 1-14 days of starting therapy. CONCLUSION: The cervicovaginal HIV-1 RNA level was positively correlated with plasma HIV-1 RNA and negatively with the CD4 cell count. The use of HAART was significantly associated with below-detectable levels of HIV-1 RNA in both plasma and the genital tract. HIV-1 RNA suppression in the genital tract may occur rapidly after initiating therapy.     

Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy

OBJECTIVE: To determine the extent to which HIV-infected patients, including those with advanced immunodeficiency, can reverse peripheral CD4 T-cell depletion while maintaining long-term viral suppression on highly active antiretroviral therapy. DESIGN: Cohort study. PARTICIPANTS: Four-hundred and twenty-three HIV-infected patients who initiated HAART prior to 1998 and achieved a viral load 1000 copies/ml. MAIN OUTCOME MEASURE: CD4 count changes. RESULTS: Among patients who maintained plasma HIV RNA levels /= 350 x 10(6)/l, respectively (all gains were significantly greater than zero; P < 0.05). Among those with a pre-therapy CD4 count of < 50 x 10(6)/l, 88% achieved a CD4 cell count of >/= 200 x 10(6)/l and 59% achieved a count of >/= 350 x 10(6)/l by year 4. Factors associated with increased CD4 cell count gains from month 3 to year 4 included lower pre-therapy CD4 cell count, younger age, female sex, and infrequent low-level viremia (versus sustained undetectable viremia). CONCLUSIONS: Most patients who achieve and maintain viral suppression on HAART continue to experience CD4 T-cell gains through 4 years of therapy. The immune system's capacity for CD4 T lymphocyte restoration is not limited by low pre-therapy CD4 counts.     

Differences in HIV-2 plasma viral load and immune activation in HIV-1 and HIV-2 dually infected persons and those infected with HIV-2 only in Abidjan, Côte D'Ivoire

OBJECTIVE: To determine whether blood plasma levels of HIV-2 RNA viral loads and immune activation markers differ between persons infected with HIV-2 only and those dually infected with HIV-1 and HIV-2. METHODS: Between September 1996 and February 2000, we collected, analyzed and compared levels of HIV-2 RNA in plasma and immune activation markers among 52 persons infected with HIV-2 alone and 75 with confirmed dual infection. We also compared viral load and immune activation in patients who were infected with HIV-1 only and those who were dually infected. RESULTS: When we conducted a CD4 T-cell count-stratified multivariate analysis of HIV-2 viral load, controlling for difference in CD4 T-cell counts, age and sex: at < 200 x 10 CD4 T cells/l, HIV-2 viral load was 2.0 log10 copies/ml lower in dually infected patients than in HIV-2 only patients (P < 0.0001). At CD4 T-cell counts between 200 x 10 and 500 x 10/l, HIV-2 viral load was 0.3 log10 copies/ml lower in dually infected patients (P = 0.45). However, at CD4 T-cells counts > 500 x 10/l, HIV-2 viral load was 0.9 log10 copies/ml higher in dually infected patients (P < 0.0001). Dually infected persons with undetectable HIV-2 viral loads had significantly higher median levels of CD8 T cells expressing CD38 (P < 0.001) and HLA-DR (P = 0.01) than HIV-2 only infected patients. CONCLUSION: These results suggest that in dual infection, the level of HIV-2 replication depends on the immune status of the patients, with HIV-1 out-replicating HIV-2 as disease progress.     

Impact of 5 years of maximally successful highly active antiretroviral therapy on CD4 cell count and HIV-1 DNA level

OBJECTIVES: To evaluate the impact on CD4 cell count and HIV-1 DNA level in peripheral blood mononuclear cells (PBMC) of long-term highly active antiretroviral therapy (HAART) in the setting of maximal success, i.e., constant plasma HIV-1 RNA load suppression. DESIGN: Retrospective analysis of patients selected for a constantly undetectable plasma HIV-1 RNA load since HAART initiation. METHODS: HIV-1 DNA was measured in PBMC using a real-time polymerase chain reaction assay. Loess estimates and regression analysis were used for modelling the variations of the CD4 cell count and HIV DNA level over time. RESULTS: The study included 41 patients chronically infected with HIV-1 who had been taking HAART for a median duration of 60.4 months and had an undetectable plasma HIV RNA load ever since the first 6 months of HAART; 25 were tested for HIV-1 DNA. The mean CD4 cell count increase was high during the first 18 months on therapy (168 x 10 cells/l per year), much lower afterwards (38 x 10 cells/l per year), independently of the baseline CD4 cell count. Most of the patients (73.2%) reached a CD4 cell count constantly > or = 400 x 10/l during follow-up. HIV-1 DNA showed a mean decrease of 0.48 log10 copies/10 PBMC during the first year, of 0.18 log10 copies/10 PBMC per year during the 2nd and 3rd years, but no significant decrease afterwards. CONCLUSIONS: These results question the benefit of very long-term maintenance of HAART in terms of CD4 gain and HIV-1 DNA reduction.     

Interleukin-2 accelerates CD4 cell reconstitution in HIV-infected patients with severe immunosuppression despite highly active antiretroviral therapy: the ILSTIM study--ANRS 082

BACKGROUND: Despite effective highly active antiretroviral therapy (HAART), some patients infected with HIV have persistently low CD4 cell counts with risk of HIV disease progression. The addition of interleukin-2, a cytokine that stimulates CD4 T lymphocyte helper cells, may benefit patients with discordant responses. METHODS: A total of 72 HIV-infected patients with CD4 cell counts of 25-200 x 10(6) cells/l (median 145) and plasma HIV RNA < 1000 copies/ml were randomized in a multicentre study to receive open-label 4.5 x 10(6) IU interleukin-2 subcutaneously twice daily for 5 days every 6 weeks plus their ongoing HAART or were maintained on HAART alone (control group). After 24 weeks, all patients received interleukin-2 therapy plus HAART up to week 80. Primary end-point was the CD4 T cell area under the curve minus baseline up to week 24. RESULTS: After four cycles of interleukin-2, in an intent-to-treat analysis, the respective median CD4 cell area under the curve minus baseline values were +51 and +11 cells in the interleukin-2 (n = 34) and the control group (n = 36) (P < 0.0001). The percentage of patients in the two groups with CD4 cell counts > 200 x 10(6) cells/l was 81% and 33%, respectively (P < 0.0001). At week 80, the median CD4 cell counts in the two groups were 380 and 270 x 10(6) cells/l, respectively. Interleukin-2 treatment was reasonably well tolerated and did not result in sustained increases in plasma HIV RNA levels. CONCLUSIONS: Administration of interleukin-2 produces significant and sustained increase in CD4 cell counts in HAART-treated patients with persistent CD4 cell counts < 200 x 10(6) cells/l.     

Response to highly active antiretroviral therapy varies with age: the UK and Ireland Collaborative HIV Paediatric Study

OBJECTIVE: To evaluate the effect of age, CD4 percentage (CD4%) and plasma HIV-1 RNA on response to highly active antiretroviral therapy (HAART) in previously untreated children. DESIGN: Cohort study. METHODS: We examined the association between age at HAART initiation, and CD4 and HIV-1 RNA response using logistic and Cox regression, adjusting for sex, route of infection and pre-HAART values. RESULTS: CD4% increases of > 10% at 6 months were more likely in younger children [odds ratio (OR), 0.84 per year, P < 0.001] and those with lower pre-HAART CD4% (OR, 0.67 per 5% higher, P < 0.001), but were not related to pre-HAART HIV-1 RNA (P = 0.6). In contrast, HIV-1 RNA suppression < 400 copies/ml at 6 months was more likely in older children (OR, 1.09 per year, P = 0.03), and was unrelated to pre-HAART HIV-1 RNA or CD4% (P > 0.3). CD4% was still increasing during the second year following HAART initiation (60% followed > 24 months). Longer-term increases in CD4% occurred faster, and decreases in HIV-1 RNA occurred more slowly in younger children. The median time to CD4% >/= 30% after initiating HAART with CD4% 相似文献   

Prognostic value of plasma HIV RNA among highly active antiretroviral therapy users

BACKGROUND: The study objective was to compare the prognostic value of plasma HIV RNA and CD4 cell count at baseline and as time-updated variables in highly active antiretroviral therapy (HAART) users for two outcomes: development of AIDS and change in CD4 cell count. METHODS: The study population comprised 387 men enrolled in the Multicenter AIDS Cohort Study who were AIDS-free and initiated HAART between 1996 and 2001. Follow-up until AIDS diagnosis (n=36, 9%) or the last AIDS-free visit was included. To determine the predictive value of combining HIV RNA and CD4 cell count, regression tree methods using recursive partitioning at pre-specified cut points for both variables were used. RESULTS: Low CD4 cell count was a strong predictor of AIDS among HAART users. However, HIV RNA showed strong prognostic value for AIDS development among those with CD4 cell counts > 250 x 10(6) cells/l, in whom an HIV RNA level > 1000 copies/ml carried a 4.6-fold greater risk of developing AIDS. HIV RNA < 5000 copies/ml was also predictive of subsequent increase in CD4 cell count with significantly higher increases among those with initial CD4 counts > 300 x 10(6) cells/l. CONCLUSION: Although, in HAART users, CD4 cell count was the primordial prognostic marker, an HIV RNA > 1000 copies/ml attained after HAART initiation was a strong predictor of the rate of subsequent CD4 cell count increase and of developing AIDS in patients whose CD4 cell counts were > 250 x 10(6) cells/l.     

Discontinuation of maintenance therapy for cytomegalovirus retinitis in HIV-infected patients receiving highly active antiretroviral therapy

OBJECTIVE: To study the safety of discontinuing cytomegalovirus (CMV) maintenance therapy among patients with cured CMV retinitis receiving highly active antiretroviral therapy (HAART). METHODS: Patients with a history of CMV retinitis who were receiving anti-CMV maintenance therapy and who had a CD4 cell count > 75 x 10(6) cells/l and a plasma HIV RNA level < 30000 copies/ml while on HAART were included in a multicentre prospective study. Maintenance therapy for CMV retinitis was discontinued at enrolment and all the patients were monitored for 48 weeks by ophthalmological examinations and by determination of CMV markers, CD4 cell counts and plasma HIV RNA levels. T helper-1 anti-CMV responses were assessed in a subgroup of patients. The primary study endpoint was recurrence of CMV disease. RESULTS: At entry, the 48 assessable patients had been taking HAART for a median of 18 months. The median CD4 cell count was 239 x 10(6) cells/l and the median HIV RNA load was 213 copies/ml. Over the 48 weeks, 2 of the 48 patients had a recurrence of CMV disease. The cumulative probability of CMV retinitis relapse was 2.2% at week 48 (95% confidence interval, 0.4-11.3) and that of all forms of CMV disease 4.2%. CMV blood markers remained negative throughout follow-up. The proportion of patients with CMV-specific CD4 T cell reactivity was 46% at baseline and 64% at week 48. CONCLUSIONS: CMV retinitis maintenance therapy may be safely discontinued in patients with CD4 cell counts above 75 x 10(6) cells/l who have been taking HAART for at least 18 months.     

Factors associated with clinical progression in HIV-2 infected-patients: the French ANRS cohort

OBJECTIVES: To identify factors associated with clinical progression in HIV-2 infected patients. DESIGN: French prospective cohort initiated in 1994. METHODS: Follow-up data are collected twice a year; viral load is assessed once a year by cellular viraemia, quantitative proviral DNA and plasma RNA. A Cox proportional-hazards model was used for studying baseline factors associated with clinical progression. RESULTS: By December 2001, 217 patients had been enrolled. At inclusion, 80%, 6% and 14% were Centers for Disease Control and Prevention (CDC) group A, B and C, respectively. Median CD4 cell count was 436 x 10(6)/l. In the 48% of positive specimens, the median plasma RNA titre was 3.0 log10 copies/ml. Mean follow-up of the 179 patients seen at least twice was 34.4 months. Of these 13 died and nine progressed to group C. Ninety-three (52%) received antiretroviral therapy during a mean of 33 months, including a protease inhibitor in 48%. The probability of remaining AIDS-free was 97% and 95% at 1 and 3 years, respectively. Independent variables associated with clinical progression were age > or = 40 years [hazard ratio (HR), 11; 95% confidence interval (CI), 1.4-91.8; P = 0.03] and plasma RNA (HR, 2.5 per additional log10 copies/ml; 95% CI, 1.3-4.7, P < 0.01). Prior group B symptoms and CD4 cell count < 200 x 10(6)/l were associated with progression to AIDS. AIDS and plasma RNA were predictive of death. CONCLUSION: Considering the limited progression rate of HIV-2 infection, combined antiretroviral therapy should be discussed in patients with high plasma RNA titres, which threshold value remains to be defined. It is recommended in case of AIDS, CDC group B symptoms or CD4 cell count < 200 x 10(6)/l.     

The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection.

BACKGROUND: Some individuals with chronic HIV-1 infection have discontinued their drug therapy with consequent plasma virus rebound. In a small number of patients, a delayed or absent rebound in plasma virus load has been noted after drug cessation, apparently associated with prior drug interruptions and autologous boosting of HIV-1 specific immune responses. We hypothesized that cyclic structured treatment interruptions structured treatment interruptions (STI) could augment HIV-1 specific immune responses in chronic HIV-1 infection, which might help to control HIV-1 replication off therapy. METHODS: We initiated an STI pilot study in 10 antiretroviral treatment-naive HIV-1 chronically infected subjects with baseline CD4 T-cell counts > 500 x 10(6) cells/l and plasma viral load > 5000 copies/ml who received highly active antiretroviral therapy (HAART) for 1 year with good response (plasma viral load < 20 copies/ml for at least 32 weeks). Three cycles of HAART interruption were performed. RESULTS: In all of the patients viral load rebounded, but doubling times increased significantly between the first and third stops (P = 0.008), and by the third stop, six out of nine subjects had a virological set-point after a median 12 months off therapy that was lower than baseline before starting HAART (ranging from 0.6 log(10) to 1.3 log(10) lower than baseline) and in four it remained stable below 5000 copies/ml. Those subjects who controlled viral replication developed significantly stronger HIV-1 specific cellular immune responses than subjects lacking spontaneous decline (P < 0.05). During viral rebounds no genotypic or phenotypic changes conferring resistance to reverse trancriptase inhibitors or protease inhibitors was detected, but mean absolute CD4 T-cell counts declined significantly, although never below 450 x 10(6)/l and the mean value at 12 months off therapy was significantly higher than the pre-treatment level (P = 0.004). CONCLUSIONS: Our findings suggest that STI in chronic HIV-1 infection might augment HIV-1-specific cellular immune responses associated with a spontaneous and sustained drop in plasma viral load in some subjects but at the potential cost of lower CD4 T-cell counts.     

A randomised, open-label comparison of three highly active antiretroviral therapy regimens including two nucleoside analogues and indinavir for previously untreated HIV-1 infection: the OzCombo1 study

BACKGROUND: Highly active antiretroviral therapy (HAART) including two nucleoside analogues and a potent protease inhibitor is standard of care initial therapy for HIV-infected adults. The best-tolerated and most potent initial HAART regimen is unknown and was investigated in this study. METHODS: One hundred and nine HIV-infected adults with no prior antiretroviral therapy, and CD4 lymphocyte counts < 500 x 10(6) cells/l or plasma HIV RNA > 30,000 copies/ml were randomized to zidovudine-lamivudine-indinavir (ZDV-3TC-IDV), stavudine-lamivudine-indinavir (d4T-3TC-IDV) or stavudine-didanosine-indinavir (d4T-ddI-IDV) for 52 weeks. The primary endpoints were plasma HIV RNA and drug-related adverse events. Other assessments were overall safety, adherence and adverse events, CD4 lymphocyte counts, cutaneous delayed type hypersensitivity (DTH) responses and quality of life (Euroqol). RESULTS: Only 58% patients had HIV RNA < 50 copies/ml plasma at 12 months, with no significant difference between the three regimes (P = 0.34). Drug-related adverse events sufficiently severe to warrant drug discontinuation were less common (P = 0.06) in patients receiving d4T-3TC-IDV (18%) than in those receiving ZDV-3TC-IDV (34%) or d4T-ddI-IDV (41%). The percentages of patients who remained on their assigned therapy with plasma HIV RNA < 50 copies/ml at 52 weeks were 60% with d4T-3TC-IDV, 53% with ZDV-3TC-IDV and 35% with d4T-ddI-IDV. Virological failure at 52 weeks was more likely in those whose adherence was estimated to be < 100% in the first 4 weeks of therapy (P = 0.02), but not in those who developed grade 3 or 4 drug-related adverse events. At 52 weeks, the mean CD4 lymphocyte count increase was 200 x 10(6) cells/l with only 7% of patients having counts lower than at baseline; DTH responses improved but remained clinically impaired in most patients. Quality of life improved significantly in all groups. CONCLUSIONS: Initial HAART regimens including IDV failed to suppress plasma HIV RNA to < 50 copies/ml in > 40% patients after only 12 months of therapy although there was significant overall improvement immunologically and in quality of life. The type of dual nucleoside combination used was less important in predicting virological failure than was imperfect adherence early in therapy. Consideration should be given to modifying a HAART regimen relatively early in non-adherent patients.     

A randomized, double-blind trial of half versus standard dose of zidovudine plus zalcitabine in Thai HIV-1-infected patients (study HIV-NAT 001). HIV Netherlands Australia Thailand Research Collaboration

BACKGROUND: Triple combination antiretroviral therapy, recommended as standard of care, is unaffordable for much of the developing world. OBJECTIVES: To establish whether half doses of zidovudine (AZT) and zalcitabine (ddC) are as effective as standard doses in a Thai population with lower body weight than Western populations and predominantly infected with HIV-1 subtype E. METHODS: A group of 116 antiretroviral naive patients, with CD4 cell counts 100-500 x 10(6) cells/l, were randomized to: AZT 200 mg three times daily plus ddC 0.75 mg three times daily versus AZT 100 mg three times daily plus ddC 0.375 mg three times daily and followed-up regularly for 48 weeks. RESULTS: The study enrolled 111 patients: 59 men and 52 women, body weight (mean +/- standard deviation) 56.4 +/- 12.3 kg, mean CD4 cell count 324 x 10(6) cells/l, mean HIV RNA 4.7 log10 copies/ml. There were no significant differences between the two groups. Twelve patients discontinued, including two deaths that were unrelated to study medication. No significant differences in adverse events were seen. Week 48 data for the standard dose and half dose arms, respectively, were mean CD4 cell count increases of 52 and 78 x 10(6) cells/l (P = 0.34), mean plasma HIV-1 RNA reduction of 1.4 and 1.1 log10 copies/ml (P = 0.10), HIV RNA of < 400 copies/ml in 52 and 20%[ (P = 0.001). Participants with higher than mean baseline CD8 cell counts (mean 1062 x 10(6) cells/l) showed greater decline in CD8 cells on standard doses. Further analysis showed improved reduction in HIV RNA (P < 0.0001) and in the percentage with undetectable HIV RNA (P = 0.0137) in the standard dose arm, corrected for baseline HIV RNA, which if < 4.75 log10 copies/ml significantly correlated with HIV RNA < 400 copies/ml at week 48. CONCLUSION: At week 48, the proportion with HIV RNA < 400 copies/ml was significantly higher in the standard dose arm; lower baseline HIV RNA correlated with better HIV RNA outcome at 48 weeks. The arms did not differ in CD4 cell response but standard doses correlated with greater CD8 cell decline.