ECG monitoring in STREAM Stage 1: can we identify those at increased risk of QT prolongation?

BACKGROUND: STREAM (Standardised Treatment Regimen of Anti-tuberculosis Drugs for Patients with Multidrug-resistant Tuberculosis) Stage 1 was a randomised trial of a Short (9-month) regimen for rifampicin-resistant TB (RR-TB). QT or QTcF prolongation ≥500 ms occurred in 31 (11%) of 282 Short regimen participants. The frequent ECG monitoring employed might be challenging for treatment programmes. This analysis aimed to determine whether those at higher risk of severe QT prolongation could be identified early for more targeted monitoring.METHODS: Data from the first month of treatment were used to investigate whether participants were at risk of developing QT/QTcF ≥500 ms. QTcF increases from baseline at different time points were examined. Absolute QTcF measurements were categorised in 5 ms increments at each time-point. The most discriminating time points and QTcF cut-offs were combined to optimise sensitivity and specificity.RESULTS: Absolute QTcF values were more discriminating than magnitude of increase from baseline. More participants who developed QT/QTcF ≥500 ms had a QTcF of respectively ≥425 ms and ≥430 ms at 4 h and Week 3 (P < 0.05) than those who did not. By combining QTcF values ≥425 ms at 4 h and ≥430 ms at Week 3, we identified high-risk participants with 97% sensitivity and 99% negative predictive value.CONCLUSION: Reduced ECG monitoring may be possible for many Short regimen participants.

Failure or relapse predictors for the STREAM Stage 1 short regimen for RR-TB.

BACKGROUND: STREAM (Standardised Treatment Regimens of Anti-tuberculosis drugs for Multidrug-Resistant Tuberculosis) Stage 1 demonstrated non-inferior efficacy of a short regimen for rifampicin-resistant TB (RR-TB) compared to a long regimen as recommended by the WHO. The present paper analyses factors associated with a definite or probable failure or relapse (FoR) event in participants receiving the Short regimen.METHODS: This analysis is restricted to 253 participants allocated to the Short regimen and is based on the protocol-defined modified intention to treat (mITT) population. Multivariable Cox regression models were built using backwards elimination with an exit probability of P = 0.157, equivalent to the Akaike Information Criterion, to identify factors independently associated with a definite or probable FoR event.RESULTS: Four baseline factors were identified as being significantly associated with the risk of definite or probable FoR (male sex, a heavily positive baseline smear grade, HIV co-infection and the presence of costophrenic obliteration). There was evidence of association of culture positivity at Week 8 and FoR in a second model and Week 16 smear positivity, presence of diabetes and of smoking in a third model.CONCLUSION: The factors associated with FoR outcomes identified in this analysis should be considered when determining the optimal shortened treatment regimen.

QT prolongation in the STREAM Stage 1 Trial.

BACKGROUND: STREAM (Standardized Treatment Regimen of Anti-TB Drugs for Patients with MDR-TB) Stage 1 demonstrated non-inferior efficacy of a shortened regimen (the Short regimen) for rifampicin-resistant TB (RR-TB) compared to the contemporaneous WHO-recommended regimen. This regimen included moxifloxacin and clofazimine, known to cause QT prolongation, and severe prolongation was more common on the Short regimen. Here we investigate risk factors for QT prolongation with the Short regimen.METHODS: Data from patients prescribed the Short regimen (n = 282) were analysed to identify risk factors for severe QT prolongation (QT/QTcF ≥500 ms or ≥60 ms increase in QTcF from baseline).RESULTS: Of the 282 patients on the Short regimen, 94 (33.3%) developed severe QT prolongation: 31 QT/QTcF ≥500 ms; 92 experienced ≥60 ms QTcF increase from baseline. The median time to QT/QTcF ≥500 ms was 20 weeks (IQR 8-28), and the time to ≥60 ms increase from baseline was 18 weeks (IQR 8-28). Prolongation ≥500 ms was most frequent in patients from Mongolia (10/22, 45.5%) compared with 3.5-11.9% at other sites, P < 0.001. Higher baseline QTcF increased risk of prolongation to ≥500 ms (QTcF ≥400 ms: OR 5.99, 95% CI 2.04-17.62).CONCLUSION: One third of patients on the Short regimen developed severe QT prolongation. QT/QTcF ≥500 ms was more common in patients from Mongolia and in those with a higher baseline QTcF, which may have implications for implementation of treatment.

Mortality and AIDS-defining events among young people following transition from paediatric to adult HIV care in the UK.

OBJECTIVES: To investigate risk of AIDS and mortality after transition from paediatric to adult care in a UK cohort of young people with perinatally acquired HIV. METHODS: Records of people aged ≥ 13 years on 31 December 2015 in the UK paediatric HIV cohort (Collaborative HIV Paediatric Study) were linked to those of adults in the UK Collaborative HIV Cohort (CHIC) cohort. We calculated time from transition to a new AIDS event/death, with follow-up censored at the last visit or 31 December 2015, whichever was the earliest. Cumulative incidence of and risk factors for AIDS/mortality were assessed using Kaplan-Meier and Cox regression. RESULTS: At the final paediatric visit, the 474 participants [51% female, 80% black, 60% born outside the UK, median (interquartile range) age at antiretroviral therapy (ART) initiation = 9 (5-13) years] had a median age of 18 (17-19) years and CD4 count of 471 (280-663) cell/µL; 89% were prescribed ART and 60% overall had a viral load ≤ 400 copies/mL. Over median follow-up in adult care of 3 (2-6) years, 35 (8%) experienced a new AIDS event (n = 25) or death (n = 14) (incidence = 1.8/100 person-years). In multivariable analyses, lower CD4 count at the last paediatric visit [adjusted hazard ratio = 0.8 (95% confidence interval: 0.7-1.0)/100 cells/µL increment] and AIDS diagnosis in paediatric care [2.7 (1.4-5.5)] were associated with a new AIDS event/mortality in adult care. CONCLUSIONS: Young people with perinatally acquired HIV transitioning to adult care with markers of disease progression in paediatric care experienced poorer outcomes in adult care. Increased investment in multidisciplinary specialized services is required to support this population at high risk of morbidity and mortality.

Investigation of the efficacy of the short regimen for rifampicin-resistant TB from the STREAM trial.

BACKGROUND: The STREAM trial demonstrated that a 9-11-month "short" regimen had non-inferior efficacy and comparable safety to a 20+ month "long" regimen for the treatment of rifampicin-resistant tuberculosis. Imbalance in the components of the composite primary outcome merited further investigation. METHODS: Firstly, the STREAM primary outcomes were mapped to alternatives in current use, including WHO programmatic outcome definitions and other recently proposed modifications for programmatic or research purposes. Secondly, the outcomes were re-classified according to the likelihood that it was a Failure or Relapse (FoR) event on a 5-point Likert scale: Definite, Probable, Possible, Unlikely, and Highly Unlikely. Sensitivity analyses were employed to explore the impact of informative censoring. The protocol-defined modified intention-to-treat (MITT) analysis population was used for all analyses. RESULTS: Cure on the short regimen ranged from 75.1 to 84.2% across five alternative outcomes. However, between-regimens results did not exceed 1.3% in favor of the long regimen (95% CI upper bound 10.1%), similar to the primary efficacy results from the trial. Considering only Definite or Probable FoR events, there was weak evidence of a higher risk of FoR in the short regimen, HR 2.19 (95%CI 0.90, 5.35), p = 0.076; considering only Definite FoR events, the evidence was stronger, HR 3.53 (95%CI 1.05, 11.87), p = 0.030. Cumulative number of grade 3-4 AEs was the strongest predictor of censoring. Considering a larger effect of informative censoring attenuated treatment differences, although 95% CI were very wide. CONCLUSION: Five alternative outcome definitions gave similar overall results. The risk of failure or relapse (FoR) may be higher in the short regimen than in the long regimen, highlighting the importance of how loss to follow-up and other censoring is accounted for in analyses. The outcome of time to FoR should be considered as a primary outcome for future drug-sensitive and drug-resistant TB treatment trials, provided sensitivity analyses exploring the impact of departures from independent censoring are also included.

Phenotypic and genotypic analyses to guide selection of reverse transcriptase inhibitors in second-line HIV therapy following extended virological failure in Uganda.

OBJECTIVES: We investigated phenotypic and genotypic resistance after 2 years of first-line therapy with two HIV treatment regimens in the absence of virological monitoring. METHODS: NORA [Nevirapine OR Abacavir study, a sub-study of the Development of AntiRetroviral Therapy in Africa (DART) trial] randomized 600 symptomatic HIV-infected Ugandan adults (CD4 cell count <200 cells/mm(3)) to receive zidovudine/lamivudine plus abacavir (cABC arm) or nevirapine (cNVP arm). All virological tests were performed retrospectively, including resistance tests on week 96 plasma samples with HIV RNA levels ≥1000 copies/mL. Phenotypic resistance was expressed as fold-change in IC(50) (FC) relative to wild-type virus. RESULTS: HIV-1 RNA viral load ≥1000 copies/mL at week 96 was seen in 58/204 (28.4%) cABC participants and 21/159 (13.2%) cNVP participants. Resistance results were available in 35 cABC and 17 cNVP participants; 31 (89%) cABC and 16 (94%) cNVP isolates had a week 96 FC below the biological cut-off for tenofovir (2.2). In the cNVP arm, 16/17 participants had resistance mutations synonymous with high-level resistance to nevirapine and efavirenz; FC values for etravirine were above the biological cut-off in 9 (53%) isolates. In multivariate regression models, K65R, Y115F and the presence of thymidine analogue-associated mutations were associated with increased susceptibility to etravirine in the cABC arm. CONCLUSIONS: Our data support the use of tenofovir following failure of a first-line zidovudine-containing regimen and shed further light on non-nucleoside reverse transcriptase inhibitor hypersusceptibility.

Residual activity of two HIV antiretroviral regimens prescribed without virological monitoring.

Virological residual activity (VRA) denotes the degree of HIV RNA suppression achieved by antiretroviral therapy in the presence of resistant virus. This concept is particularly important in resource-limited settings, where rapid switching after detection of virological failure may not be feasible. Using data from the NORA trial, we estimated VRA for two regimens-zidovudine-lamivudine-abacavir (ZDV-3TC-ABC) and zidovudine-lamivudine-nevirapine (ZDV-3TC-NVP)-and related this to the phenotypic drug sensitivity of the component drugs in the two regimens. Plasma samples at weeks 0, 48, and 96 were retrospectively assayed for HIV-1 RNA, and genotypic/phenotypic resistance testing was performed if HIV-1 RNA exceeded 1,000 copies/ml. Virological residual activity (VRA) was defined as the difference between log(10)(HIV RNA) at week 48 or 96 and week 0 and related to 50% inhibitory concentration (IC(50)) relative to wild-type virus for ZDV and ABC (fold change [FC]). Twenty-seven samples in the ZDV-3TC-NVP group and 56 in the ZDV-3TC-ABC group contributed to the analysis. Mean VRA was significantly higher in the ZDV-3TC-ABC group than in the ZDV-3TC-NVP at week 48 (1.62 versus 0.90) and week 96 (1.29 versus 0.78). There was a weak and nonsignificant relationship between VRA and ZDV FC, with VRA decreasing by 0.1 log(10) copies/ml per 2-fold increase in ZDV. The association with ABC FC was much stronger, with a marked reduction in VRA occurring at ABC FC values greater than approximately 2. This information should be considered in future treatment guidelines relevant to resource-poor settings.

Hyperlactataemia in HIV-infected subjects initiating antiretroviral therapy in a large randomized study (a substudy of the INITIO trial).

OBJECTIVE: The aim of the study was to evaluate the predictive value of clinical and molecular risk factors, including peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), for the development of lactic acidosis (LA) and symptomatic hyperlactataemia (SHL). METHODS: In a substudy of a large multicentre, randomized trial of three antiretroviral regimens, all containing didanosine (ddI) and stavudine (d4T), in antiretroviralnaïve, HIV-1-infected patients, patients with LA/SHL ('cases') were compared with those without LA/SHL in a univariate analysis, with significant parameters analysed in a multivariate model. In a molecular substudy, PBMC mtDNA and mtRNA from cases and matched controls at baseline and time of event were examined. RESULTS: In 911 subjects followed for a median of 192 weeks, 24 cases were identified (14 SHL and 10 LA). In univariate analysis, cases were more likely to be female (P=0.05) and to have a high body mass index (BMI) (P=0.02). In multivariate analyses, only BMI remained an independent predictor of the development of LA/SHL (P=0.03). Between cases and controls there was no significant difference in mtDNA copy number at baseline (389 vs. 411 copies/cell, respectively; P=0.60) or at time of event (329 vs. 474 copies/cell, respectively; P=0.21), in the change in mtDNA copy number from baseline to event (-65 vs. +113 copies/cell, respectively; P=0.12), in mtRNA expression at baseline or time of event, or in the change in mtRNA expression from baseline to event. CONCLUSION: The development of LA/SHL was associated with increased BMI, but PBMC mtDNA and mtRNA did not predict LA/SHL. This demonstrates the ineffectiveness of routine measurement of PBMC mtDNA in patients on ddI and d4T as a means of predicting development of LA/SHL.

Restoration of anti-tetanus toxoid responses in patients initiating highly active antiretroviral therapy with or without a boost immunization: an INITIO substudy.

INITIO is an open-labelled randomized trial evaluating first-line therapeutic strategies for human immunodeficiency virus-1 (HIV-1) infection. In an immunology substudy a tetanus toxoid booster (TTB) immunization was planned for 24 weeks after initiation of highly active antiretroviral therapy (HAART). All patients had received tetanus toxoid immunization in childhood. Generation of proliferative responses to tetanus toxoid was compared in two groups of patients, those receiving a protease inhibitor (PI)-sparing regimen (n = 21) and those receiving a PI-containing (n = 54) regimen. Fifty-two participants received a TTB immunization [PI-sparing (n = 15), PI-containing (n = 37)] and 23 participants did not [PI-sparing (n = 6) or PI-containing (n = 17)]. Cellular responses to tetanus antigen were monitored by lymphoproliferation at time of immunization and every 24 weeks to week 156. Proportions with a positive response (defined as stimulation index > or = 3 and Delta counts per minute > or = 3000) were compared at weeks 96 and 156. All analyses were intent-to-treat. Fifty-two participants had a TTB immunization at median 25 weeks; 23 patients did not. At weeks 96 and 156 there was no evidence of a difference in tetanus-specific responses, between those with or without TTB immunization (P = 0.2, P = 0.4). There was no difference in the proportion with response between those with PI-sparing or PI-containing regimens at both time-points (P = 0.8, P = 0.7). The proliferative response to tetanus toxoid was unaffected by initial HAART regimen. Anti-tetanus responses appear to reconstitute eventually in most patients over 156 weeks when treated successfully with HAART, irrespective of whether or not a TTB immunization has been administered.

Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial.

BACKGROUND: Antiretroviral therapy has greatly reduced HIV mortality and morbidity. However, the best sequence of regimens and implications of initial regimen for long-term therapeutic success are not well defined. METHODS: In INITIO, a large international randomised trial, we compared antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (didanosine+stavudine) plus either a non-nucleoside reverse transcriptase inhibitor (efavirenz, EFV) or a protease inhibitor (nelfinavir, NFV), or both (EFV/NFV), in patients with HIV-1 infection who had not previously received antiretroviral drugs. Primary outcomes were proportion with undetectable HIV RNA in plasma, and change in CD4 count from baseline at 3 years. Analyses were by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN44582462. FINDINGS: We followed up 911 participants (297 EFV, 311 NFV, 303 EFV/NFV). At 3 years, the proportion with HIV RNA less than 50 copies per mL was highest in the EFV group (188 [74%] EFV, 162 [62%] NFV, 155 [62%] EFV/NFV; p=0.004). Mean (95% CI) increases in CD4 count were 316x10(6) cells per L (288-343) for EFV, 289x10(6) cells per L (262-316) for NFV, and 274x10(6) cells per L (231-291) for EFV/NFV (p=0.1). Fewer participants in the EFV group than in the other groups stopped adequate antiretroviral therapy for more than 30 days (p=0.005). Participants in the EFV/NFV group had shorter time to stopping the initial regimen (p<0.0001) and to a treatment modifying adverse event (p=0.04) than those in the other groups. INTERPRETATION: Starting antiretroviral therapy with a three-drug/two-class regimen including efavirenz was better than starting with regimens including nelfinavir or efavirenz plus nelfinavir in terms of virological suppression and durability of the initial regimen. The shorter time on adequate antiretroviral therapy or to a treatment-modifying adverse event might explain the absence of additional benefit for the four-drug regimen.

Randomised controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream, and podophyllin in the treatment of genital warts.

OBJECTIVES: To evaluate the efficacy and cost effectiveness of self applied podophyllotoxin 0.5% solution and podophyllotoxin 0.15% cream, compared to clinic applied 25% podophyllin in the treatment of genital warts over 4 weeks. METHODS: We conducted a randomised controlled trial in 358 immunocompetent men and women with genital warts of 3 months' duration or less. RESULTS: In the principal analysis both podophyllotoxin solution (OR 2.93, 95% CI 1.56 to 5.50) and podophyllotoxin cream (OR 1.97, 95% CI 1.04 to 3.70) were associated with significantly increased odds of remission of all warts compared to podophyllin. We performed two further analyses. When subjects defaulting from follow up were assumed to have been cured odds of remission of all warts were also significantly increased both for podophyllotoxin solution (OR 3.04, 95% CI 1.68 to 5.49) and for podophyllotoxin cream (OR 2.46, 95% CI 1.38 to 4.40). When subjects defaulting from follow up were assumed not to have been cured odds of remission of all warts were significantly increased for podophyllotoxin solution (OR 1.92, 95% CI 1.13 to 3.27), but not for podophyllotoxin cream (OR 1.17, 95% CI 0.69 to 2.00). Local side effects were seen in 24% of subjects, and recurrence of warts within 12 weeks of study entry in 43% of all initially cleared subjects, without statistically significant differences between the treatment groups. Direct, indirect, and total costs were similar across the three treatment groups. Podophyllotoxin solution was the most cost effective treatment, followed by podophyllotoxin cream, with podophyllin treatment being the least cost effective. CONCLUSIONS: Self treatment of anogenital warts with podophyllotoxin showed greater efficacy and cost effectiveness than clinic based treatment with podophyllin.

Rifapentine and isoniazid in the continuation phase of a 6-month regimen. Final report at 5 years: prognostic value of various measures.

SETTING: Clinical trial in 672 patients with newly diagnosed pulmonary tuberculosis in Hong Kong. After an initial 2 months of a four-drug intensive phase consisting of thrice-weekly streptomycin, isoniazid, rifampicin and pyrazinamide (SHRZ), a random allocation was made to a continuation phase of once-weekly 600 mg rifapentine + 15 mg/kg isoniazid (HRp1), HRp1 given in 2 of every 3 weeks (HRp1.2/3), or to thrice-weekly isoniazid + rifampicin (HR3), the standard treatment in Hong Kong. OBJECTIVE: Final report evaluating adverse events (46 relapses and one failure) after 5 years and the prognostic influence of various factors. METHODS: Kaplan-Meier analysis of adverse events and Cox proportional hazards analysis of prognostic factors. RESULTS: The two rifapentine regimens, HRp1 and HRp1.2/3 had similar final rates of adverse events of 10.8% and 11.7%, respectively, compared to 4.2% for the HR3 regimen (P = 0.02 and 0.009, respectively). In the initial univariate proportional hazards analysis, adverse events were significantly related to the regimen, age, sex, pretreatment radiographic extent of disease and cavitation, and also to sputum culture at 2 months. In the final multivariate analysis, after step-wise removal of non-significant factors, adverse events were related only to the regimen, patients' sex and pretreatment radiographic extent of disease. Elderly male patients were more at risk of an adverse event, as were those with more severe disease. Adverse events occurred at life table rates of 9.0% in patients with drug-sensitive strains and in 8.9% of those with initially isoniazid-resistant organisms at 5 years. CONCLUSIONS: The two rifapentine regimens were unsatisfactory because of their high incidence of adverse events. Isoniazid appeared not to contribute to preventing relapse. Further studies with increased rifapentine dosage are necessary.

The activity of low-clearance liposomal amikacin in experimental murine tuberculosis.

Most of the amikacin in low-clearance liposomal amikacin is excreted very slowly, offering the possibility of maintaining effective treatment of pulmonary tuberculosis with widely separated supervised doses. As a preliminary to explorations in humans, its efficacy was assessed in acute experimental murine tuberculosis by weekly counts of viable bacilli in spleen and lungs over a 4 week period. Liposomal amikacin in dosages of 160, 80 and 40 mg/kg given iv three times a week was 2.4-5.0 times more active than free amikacin and 6.6-6.7 times more active than streptomycin with the non-liposomal drugs given im five times a week. When the free amikacin and the streptomycin were also given iv three times a week, liposomal amikacin was 2.7-2.9 times more active than free amikacin and 3.7-5.6 more active than streptomycin. In a model of chronic tuberculosis, initial BCG vaccination was followed by challenge with virulent Mycobacterium tuberculosis and a 2 week stabilization period. Thereafter, treatment with liposomal amikacin 160 and 80 mg/kg three times a week for the first 4 weeks and then once a week for a further 4 weeks, had greater initial bactericidal activity than free amikacin 160 mg/kg five times a week, but had less eventual sterilizing activity than five times a week oral isoniazid 25 mg/kg or rifampicin 15 mg/kg. Although low-clearance liposomes increased the safety, potency and dosing interval of amikacin in these models, all aminoglycosides, including liposomal amikacin, were only bactericidal in the presence of bacillary metabolism and growth.

Timing and interpretation of tests for diagnosing perinatally acquired hepatitis C virus infection.

The diagnosis of hepatitis C virus (HCV) infection in children born to HCV-infected women is based on serologic assays and HCV RNA measurement by PCR. Interpretation of the results of these tests is hampered by uncertainty about the age distribution of loss of maternal antibody and the sensitivity and specificity of PCR at different ages. On the basis of findings from a recent vertical transmission study, we estimated the posttest probability of a child's being infected or uninfected under several test result scenarios. These estimates may assist clinicians in assessing the likelihood of infection in an individual child and in using the currently available assays cost effectively.

Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission.

BACKGROUND: Little information is available about the timing of mother-to-child transmission of hepatitis C virus (HCV), and no interventions to decrease transmission rates have been identified. We examined the effect of risk factors, including mode of delivery, on the vertical transmission rate. METHODS: Data from HCV-infected women and their infants from three hospitals in Ireland and from a British Paediatric Surveillance Unit study of infants born to HCV-infected mothers were used to estimate the vertical transmission rate and risk factors for transmission. We used a probabilistic model using methods that simultaneously estimated the time to HCV-antibody loss in uninfected infants and the diagnostic accuracy of PCR tests for HCV RNA. FINDINGS: 441 mother-child pairs from the UK (227) and Ireland (214) were included. 50% of uninfected children became HCV-antibody negative by 8 months and 95% by 13 months. The estimated specificity of PCR for HCV RNA was 97% (95% CI 96-99) and was unrelated to age; sensitivity was only 22% (7-46) in the first month but rose sharply to 97% (85-100) thereafter. The vertical transmission rate was 6.7% (4.1-10.2) overall, and 3.8 times higher in HIV coinfected (n=22) than in HIV-negative women after adjustment for other factors (p=0.06). No effect of breastfeeding on transmission was observed, although only 59 women breastfed. However, delivery by elective caesarean section before membrane rupture was associated with a lower transmission risk than vaginal or emergency caesarean-section delivery (odds ratio 0 [0-0.87], p=0.04, after adjustment for other factors). INTERPRETATION: The low sensitivity of HCV RNA soon after birth and the finding of a lower transmission rate after delivery by elective caesarean section suggest that HCV transmission occurs predominantly around the time of delivery. If the findings on elective caesarean section are confirmed in other studies, the case for antenatal HCV testing should be reconsidered.

How generalizable are the results of large randomized controlled trials of antiretroviral therapy?

OBJECTIVES: To examine the generalizability of two large randomized controlled clinical trials of antiretroviral therapy in HIV-infected individuals. METHODS: The demographic, clinical and laboratory characteristics of HIV-infected participants in two antiretroviral trials (Concorde and Delta) at three study sites were compared with those of two other groups of patients to whom the trial results would be applicable: eligible patients who were screened for the trials but who did not enrol, and eligible patients who were not approached or screened for the trials. RESULTS: Among enrolled participants in the Concorde and Delta trials there was an under-representation of patients who had acquired HIV infection heterosexually (P = 0.014) or through injecting drug use (P = 0.03), and a greater representation of homosexual men (P < 0.001) compared to non-enrolled participants. Trial participants in Concorde had significantly less advanced immunosuppression compared to non-trial participants (P = 0.0001), while in Delta the converse was true. Concorde participants were also much less likely to be lost to follow-up for more than a year (9%) compared to eligible but unscreened patients (40%) (P < 0.001), and screened but unenrolled patients (22%) (P = 0.035). CONCLUSIONS: In applying the findings of large randomized clinical trials, it is important to establish whether there are systematic differences between the characteristics of trial participants and eligible non-participants, which might affect the generalizability of the study results. A log of the characteristics of enrolled as well as eligible but non-enrolled patients should be maintained so that the representativeness of the trial population can be evaluated.

Are HIV-infected patients with rapid CD4 cell decline a subgroup who benefit from early antiretroviral therapy?

We have developed a model to determine whether asymptomatic HIV-infected individuals who have a rapid CD4 cell decline are a subgroup who might benefit from early antiretroviral therapy. Data were obtained from a subgroup of participants in the Concorde and EACG020 trials, two randomized, double-blind, comparative trials of immediate (IMM) versus deferred (DEF) zidovudine therapy in asymptomatic HIV-infected individuals. The subgroup comprised 297 patients (IMM = 154, DEF = 143) who had at least one CD4 cell count before and after randomization. The median CD4 cell count at randomization was 491 x 10(6)/L, and the median follow-up was 61 months. The rate of CD4 decline before and after randomization was estimated using multi-level linear regression analysis, and patients were stratified into quartiles according to the rate of CD4 cell decline before randomization. Outcome measures were the development of AIDS, a 50% drop in CD4 count from the baseline, and death. A Cox proportional hazards model was used to examine whether the effect of zidovudine on disease progression varied according to the previous rate of CD4 decline. We found that a more rapid rate of CD4 decline before randomization was associated with a greater reduction in the rate of CD4 decline following IMM antiretroviral therapy (r = -0.5, P = 0.03). The greatest risk reduction in disease progression with IMM antiretroviral therapy was seen in the quartile of patients with the highest rate of CD4 decline (> or = 26 x 10(6) cells/L per 6 months) (hazards ratio (HR) = 0.61, 95% CI = 0.35-1.05). However, this effect was statistically significant in only the Concorde trial (HR = 0.48, 95% CI = 0.29-0.89). In contrast, we found no evidence in the EACG020 trial of any trend towards greater benefit in those with the most rapid CD4 cell decline. These findings suggest that asymptomatic patients with rapid CD4 cell decline are a subgroup likely to benefit from early antiretroviral therapy. This analytic approach should now be replicated in trials of combination therapy, and these should include viral load data.

Association between a defective CCR-5 gene and progression to disease in HIV infection.

We measured the effect(s) of CCR-5 genotype on disease progression by studying the frequency of a defective CCR-5 delta32 allele within a cohort of long-term infected individuals. An elevated frequency of CCR-5 delta32 heterozygotes within the cohort compared with a control population of blood donors was observed. An association between progression rate and CCR-5 delta32 heterozygosity was observed. Furthermore, analysis of proviral DNA V3 sequences from a subset of the cohort predicted that the majority of individuals (39 of 44) were infected with viruses predicted to utilize the beta-chemokine receptor CCR-5. The marked association between CCR-5 genotype and disease progression observed in this study may be a consequence of the predicted low frequency of CXCR-4-utilizing viruses present within the selected cohort.