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BackgroundTo analyse the effect of drug resistance mutations (DRM) on CD4+T-cell (CD4) trends in HIV-positive people maintained on virologically failing anti-retroviral therapy (ART).MethodsIndividuals from two large cohorts experiencing virological failure (VF) while maintained on ART with ≥1 CD4 count and ≥1 resistance test were included. CD4 slopes were estimated using linear mixed models. Principal component analysis (PCA) was used to assess the effect of clusters of mutations, defined using extracted component based scores from the PCA, on CD4 decline.Results5,357 individuals contributing 7,661 VF episodes were included: any DRM were detected in 88.8% of episodes. After adjustment, CD4 counts declined less steeply during episodes where DRM were detected compared to episodes with no DRM (difference =28 cells/mm3/year, 95% CI =18, 39; PConclusionsDetection of resistance and of certain DRM during VF of ART has a small but significant favourable effect on CD4 decline.

Background Antiretroviral (ART) drugs have been associated with higher triglycerides (TG), higher total cholesterol (TC) and lower high-density lipoprotein cholesterol (HDL-C) levels. Associations between lipid levels with HIV viraemia and immunosuppression in the presence of ART remain unclear. Methods Participants from the D:A:D study with at least one TG/TC/HDL-C measurement were included. Linear mixed effect models were used to determine the association of ART, viral load (VL), nadir and current CD4+ T-cell count and previous AIDS diagnosis with lipids. Results Of 49,717 participants, 90%, 92% and 80% contributed at least one TG/TC/HDL-C measurement (median follow-up 6.8, 6.8 and 5.0 years, respectively). Predicted mean (95% CI) baseline levels for TG, TC and HDL-C (mmol/l), were 2.10 (2.05, 2.14), 4.94 (4.91, 4.98) and 1.08 (1.07, 1.10), respectively. Lopinavir was associated with the worst TG profile, (27.2% higher levels compared to atazanavir; 95% CI 25.2%, 29.2%), and darunavir had a similar profile as atazanavir. The nucleoside pair lamivudine/tenofovir was associated with the most favourable TG profile (-2.8%; -3.5%, -2.0%) compared with emtricitabine/tenofovir, whereas lamivudine/abacavir (+10.2%; +9.3%, +11.2%) and lamivudine/ stavudine (+8.0%; +6.9%, +9.0%), were associated with the worst. Raltegravir was associated with lower TG (-5.2%; -6.4%, -3.9%), and nevirapine had a more favourable HDL-C profile (+11.3%; +10.8%, +11.7%) than efavirenz (+5.3%; 5.0%, 5.7%), compared to atazanavir. Higher VLs were associated with lower TG/TC/HDL-C, whereas higher CD4+ T-cell counts were associated with higher TG/TC/HDL-C. Conclusions TG, TC and HDL-C levels, which generally improved over time, are dependent on ART, viraemia and, to a lesser extent, immunosuppression.

To analyse the effect of drug resistance mutations (DRM) on CD4Individuals from two large cohorts experiencing virological failure (VF) while maintained on ART with ≥1 CD4 count and ≥1 resistance test were included. CD4 slopes were estimated using linear mixed models. Principal component analysis (PCA) was used to assess the effect of clusters of mutations, defined using extracted component based scores from the PCA, on CD4 decline.5,357 individuals contributing 7,661 VF episodes were included: any DRM were detected in 88.8% of episodes. After adjustment, CD4 counts declined less steeply during episodes where DRM were detected compared to episodes with no DRM (difference =28 cells/mmDetection of resistance and of certain DRM during VF of ART has a small but significant favourable effect on CD4 decline.

Background We analysed the influence of gender on use and outcomes of first-line HAART in a UK cohort. Methods Analyses included heterosexuals starting HAART from 1998-2007 with pre-treatment CD4+ T-cell count 3 and viral load (VL)>500 copies/ml. Virological suppression (500 copies/ml), CD4+ T-cell counts at 6 and 12 months, clinical events and treatment discontinuation/switch in the first year of HAART were compared using linear, logistic and Cox regression. Results Compared with women ( n=2,179), men ( n=1,487) were older and had lower CD4+ T-cell count and higher VL at start of HAART. Median follow-up was 3.8 years (IQR 2.0-6.2). At 6 and 12 months, 72.7% and 75.3% had VL≤50 copies/ml, with no large differences between genders at either time after adjustment for confounders (6 months, OR 0.92 [95% CI 0.76-1.13]; 12 months, OR 1.06 [95% CI 0.85-1.31]). Overall, 79.4% patients achieved virological suppression and 19.2% experienced virological rebound, without gender differences, although men had an increased risk of rebound after excluding pregnant women (adjusted relative hazard [RH] 1.33 [95% CI 1.04–1.71]). Mean CD4+ T-cell count increases at 6 and 12 months were, respectively, 11 2 and 156 cells/mm3 overall, with mean differences between men and women of -14.6 cells/mm3 (95% CI -24.6—4.5) and -12.1 cells/mm3 (95% CI -24.4– 0.2) at 6 and 12 months, respectively. Clinical progression was similar in men and women, but men were less likely to experience treatment discontinuation/switch (adjusted RH 0.72 [95% CI 0.63–0.83]). Conclusions Despite higher discontinuation rates among women, men had an increased risk of virological rebound and slightly poorer CD4+ T-cell count responses. Identifying the reasons underlying treatment discontinuation/switch may help optimize treatment strategies for both genders.

Background Guidelines suggest that patients on continuous antiretroviral therapy for >4 months with current viral load (VL)>1,000 copies/ml should be tested for resistance. There are limited data showing the frequency of resistance testing in routine clinical practice following these recommendations. Methods In EuroSIDA, virological failure (VF) was defined as confirmed VL>1,000 copies/ml after ≥4 months continuous use of any antiretroviral in a ≥3-drug regimen started during or after 2002. We assessed whether a resistance test was performed around VF (from 4 months before to 1 year after VF) and used logistic regression analysis to assess factors associated with having a resistance test. Results A total of 1,090 patients experienced VF a median 8.1 months (range 4 months to 6.3 years) after starting their regimen. There were 395 (36.2%; 95% CI 33.4–39.1) patients with a resistance test around the time of VF. Predictors of having a resistance test following VF include availability of a resistance test earlier than 4 months before VF (OR 2.20, 95% CI 1.77–2.75 for yes versus no; PConclusions This analysis suggests a delay in genotypic testing after VF that seems longer than expected given current treatment guidelines. This delay is highly variable across Europe.

BackgroundPatients receiving combination antiretroviral therapy (cART) might continue treatment with a virologically failing regimen. We sought to identify annual change in CD4+T-cell count according to levels of viraemia in patients on cART.MethodsA total of 111,371 CD4+T-cell counts and viral load measurements in 8,227 patients were analysed. Annual change in CD4+T-cell numbers was estimated using mixed models.ResultsAfter adjustment, the estimated average annual change in CD4+T-cell count significantly increased when viral load was 3, 95% confidence interval [CI] 26.6–34.3), was stable when viral load was 500–9,999 copies/ml (3.1 cells/mm3, 95% CI -5.3–11.5) and decreased when viral load was ≥10,000 copies/ml (-14.8 cells/mm3, 95% CI -4.5– - 25.1). Patients taking a boosted protease inhibitor (PI) regimen had more positive annual CD4+T-cell count changes than patients taking other regimens for any given viral load strata: 30.9 cells/mm3(95% CI 27.7–34.1) when viral load was 3(95% CI -2.1–30.4) when viral load was 500–9,999 copies/ml and -19.9 cells/mm3(95% CI -36.6– -3.3) when viral load was ≥10,000 copies/ml. By contrast, among patients taking a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, the CD4+T-cell count significantly decreased when the viral load was 500–9,999 copies/ml (-18.6 cells/mm3, 95% CI -33.8– - 3.5) and decreased at a faster rate when the viral load was ≥10,000 copies/ml (-44.4 cells/mm3, 95% CI -62.0– -26.9; P=0.0012, test for interaction).ConclusionsOn average, CD4+T-cell counts did not significantly decrease until the viral load exceeded 10,000 copies/ml in patients treated with a boosted PI-containing cART regimen, but decreased in patients taking an NNRTI-based cART regimen when viral load was 500–9,999 copies/ml.

Background Data on a link between HCV or HBV infection and the development of cardiovascular disease among HIV-negative and HIV-positive individuals are conficting. We sought to investigate the association between HBV or HCV infection and myocardial infarction in HIV-infected individuals. Methods The prospective observational database of the D:A:D collaboration of 11 cohorts of HIV-infected individuals, including 212 clinics in Europe, the United States and Australia was used. Multivariate Poisson regression was used to assess the effect of HCV or HBV infection on the development of myocardial infarction after adjustment for potential confounders, including cardiovascular risk factors, diabetes mellitus and exposure to antiretroviral therapy. Results Of 33,347 individuals, 517 developed a myocardial infarction over 157,912 person-years, with an event rate of 3.3 events/1,000 person-years (95% confidence interval [CI] 3.0–3.6). Event rates (95% CIs) per 1,000 person-years in those who were HCV- seronegative and HCV-seropositive were 3.3 (3.0–3.7) and 2.7 (2.2–3.3), respectively, and for those who were HBV-seronegative, had inactive infection or had active infection were 3.2 (2.8–3.5), 4.2 (3.1–5.2) and 2.8 (1.8–3.9), respectively. After adjustment, there was no association between HCV seropositivity (rate ratio 0.86 [95% CI 0.62–1.19]), inactive HBV infection (rate ratio 1.07 [95% CI 0.79–1.43]) or active HBV infection (rate ratio 0.78 [95% CI 0.52–1.15]) and the development of myocardial infarction. Conclusions We found no association between HBV or HCV coinfection and the development of myocardial infarction among HIV-infected individuals.

Background Combination antiretroviral therapy (cART) may vary in ability to suppress viral load and increase CD4+ T-cell count in people infected with different HIV-1 subtypes, possibly due to differences in resistance development. Antiretroviral drugs have predominantly been developed in Western Europe/North America on the basis of the most prevalent subtype, B. However, non-B subtypes are increasingly spreading worldwide. Objective To compare virological and immunological response to cART between patients infected with B and non-B subtypes across Europe. Design EuroSIDA prospective, observational cohort with 11,928 HIV-1-infected patients. Methods Response to cART was analysed in patients with subtypes determined pre-cART, via multivariable logistic regression on the first measurements 6–12 months after starting cART. A virological response was defined as a viral load + T-cell count increase of ≥100 cells/mm3. Results Forty-five percent of patients were antiretroviral naive at initiation of cART. Virological suppression was achieved by 58% of 689 subtype-B-infected patients and 66% of 102 non-B-infected patients ( P=0.159). After adjustment for potential confounders, there was no significant difference in odds of achieving virological suppression (non-B compared with B; odds ratio [OR]: 1.05, 95% confidence interval [CI]: 0.58–1.93, P=0.866). An immunological response was achieved by 43% of 753 B-infected patients and 48% of 114 non-B-infected patients ( P=0.334). After adjustment, there was no significant difference in odds of an immunological response (OR: 1.17, 95% CI: 0.73–1.87, P=0.524). Conclusions There was no evidence of significant differences in virological or immunological response to cART between patients infected with HIV-1 B and non-B subtypes.

Introduction It is unknown whether the increased risk of toxicities in antiretroviral-naive HIV-infected patients initiating nevirapine-based (NVPc) combination antiretroviral therapy (cART) with high CD4+ T-cell counts is also observed when NVPc is initiated in cART-experienced patients. Patients and methods 1,571 EuroSIDA patients started NVPc after 1/1/1999, with CD4+ T-cell counts and viral load measured in the 6 months before starting treatment, and were stratified into four groups based on CD4+ T-cell counts at initiation of NVPc (high [H], >400/mm3 or >250/mm3 for male or female, respectively, or low [L], ≤400/mm3 or ≤250/mm3 for male or female) and prior antiretroviral experience (antiretroviral-naive [N] or -experienced [E]). Cox proportional hazards models compared the risks of discontinuation of nevirapine due to toxicities or patient/physician choice (TOXPC). Results After adjustment, there was a significantly lower risk of discontinuation of nevirapine due to TOXPC in the HE group ( n=588; proportion discontinued by 3/12 months: 10/17%, respectively) than in HN (n=62; 21/32% respectively; overall relative hazard [RH]: 0.56; 95% confidence interval [CI]: 0.34–0.94; P=0.027). This difference was most pronounced during the first 3 months of NVPc (RH: 0.44; 95% CI: 0.23–0.87; P=0.017). There were no deaths in the 6 months after starting NVPc resulting from exposure to Conclusions Results from this non-randomized study suggest that NVPc might be safer to initiate in antiretro-viral-experienced than in antiretroviral-naive patients with high CD4+T-cell counts.

Background It has been suggested that a lower pre-highly active antiretroviral therapy (HAART) CD4 count nadir may lead to a greater risk of experiencing HAART-related toxicity. We investigated the relationship between the pre-HAART CD4 count nadir, HAART and the occurrence of laboratory-defined toxicities. Methods Previously antiretroviral-naive individuals starting HAART at the Royal Free Hospital, London, UK, were included. Drug discontinuation, increases in total cholesterol (by >1mmol/l), alanine aspartate transferase/ alanine aminotransferase (AST/ALT) (by >2.5 times the upper limit of normal), bilirubin (by >2.5 times the upper limit of normal), triglycerides (by >1 mmol/l) and decreases in haemoglobin (by >2 g/dl) were assessed. Results 377/847 (45%) individuals starting HAART stopped at least one antiretroviral within the first 48 weeks. Lower CD4 nadirs were not associated with a greater rate of discontinuing antiretrovirals (adjusted hazard ratio (HR)=1.04 per 100 cells/mm3 higher; 95% confidence intervals (CI) 0.99–1.10; P=0.15). 70/297 (24%), 39/192 (20%) and 73/358 (20%) with a CD4 cell nadir of 0–100, 100–200 and 200+ cells/mm3, respectively, stopped for toxicity reasons; 11/297 (4%), 5/192 (3%) and 3/358 (1%) stopped for reasons of insufficient efficacy; 63/297 (21%), 33/192 (17%) and 80/358 (22%) stopped for other reasons ( P=0.1). Reasons for stopping were similar between CD4 nadir groups. Lower CD4 nadirs were not associated with an increased risk of hypercholesterolaemia, anaemia, hypertriglyceridaemia or increases in AST/ALT but were associated with increased incidence of hyperbilirubinaemia (HR=0.67 per 100 cells/mm3 higher; 95% CI 0.49–0.92; P=0.01). Discussion Lower CD4 nadirs were not found to be associated either with discontinuing an antiretroviral or with a higher risk of toxicity, except for an increased risk of experiencing an increase in bilirubin levels.

The results from the HPTN 052 trial have increased the focus on use of antiretroviral therapy (ART) for prevention of HIV transmission; however, condom use also effectively prevents HIV transmission. Studies in heterosexual serodiscordant couples with viral suppression have so far only reported follow-up data for 330 couple-years when condoms were not being used. Data are even more limited for anal sex in men who have sex with men. Additional data on the effectiveness of ART as prevention when practicing condom-less sex is urgently needed.

This is the author’s version of a work accepted for publication by International Medical Press. Changes resulting from the publishing process, including peer review, editing and formatting, might not be reflected in this document. A definitive version was published in Antiviral Therapy, [7, 1], 2002, © 2002 International Medical Press, There is an increasing proportion of HIV-positive patients exposed to all licensed classes of antiretrovirals, and the response to salvage regimens may be poor. Among over 8500 patients in EuroSIDA, the proportion of treated patients exposed to nucleosides, protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitor (NNRTI) increased from 0% in 1996 to 47% in 2001. Four-hundred-and-thirteen patients, who had failed virologically two highly active antiretroviral therapy (HAART) regimens and experienced all three main drug classes, started a salvage regimen of at least three drugs, in which at least one new PI or NNRTI was included. Median viral load was 4.7 log copies/ml [Interquartile range (IQR) 4.2-5.2], CD4 lymphocyte count 150/mm3 (IQR 60-274/mm3) and follow-up 14 months. Of these patients, 283 (69%) subsequently experienced at least a 1 log decline in viral load and 202 (49%) achieved a viral load < 500 copies/ml. Conversely, the CD4 count halved from the baseline value in 88 (21%), and 45 (11%) experienced a new AIDS-defining disease. In multivariable analyses, a 1 log viral load reduction was related to baseline viral load [relative hazard (RH) 1.27 per 1 log higher; P = 0.008], a previous viral load of less than 500 copies/ml (RH 1.69; P = 0.002), more recent initiation of the regimen (RH 1.36 per year more recent; P = 0.02), number of new drugs in the regimen (RH 1.20 per drug; P = 0.02), time since start of antiretroviral therapy (RH 0.94 per extra year; P = 0.035) and time spent on HAART with viral load > 1000 copies/ml (RH 0.96 per extra month; P = 0.0001). Analysis of factors associated with CD4 count decline and new AIDS disease also indicated improved outcomes in more recent times and a tendency for a better response in those starting more new drugs, but no relationship with the total number of drugs. Outcomes in people starting salvage regimens appear to depend on the number of new drugs started but not on the total number of drugs being used.

To assess the relation between resistance to antiretroviral drugs for treatment of HIV-1 infection and virological response to therapy, results from 12 different studies were re-analysed according to a standard data analysis plan. These studies included nine clinical trials and three observational cohorts. The primary end-point in our analyses was virological failure by week 24. Baseline factors that were investigated as predictors of virological failure were plasma HIV-1 RNA, the number and type of new antiretroviral drugs in the regimen, and viral susceptibility to the drugs in the regimen, determined by genotyping or phenotyping methods. These analyses confirmed the importance of both genotypic and phenotypic drug resistance as predictors of virological failure, whether these factors were analysed separately or adjusted for other baseline confounding factors. In most of the re-analysed studies, the odds of virological failure were reduced by about twofold for each additional drug in the regimen to which the patient's virus was sensitive by genotyping methods, and by about two- to threefold for each additional drug that was sensitive by phenotyping.

The results from the HPTN 052 trial have increased the focus on use of antiretroviral therapy (ART) for prevention of HIV transmission; however, condom use also effectively prevents HIV transmission. Studies in heterosexual serodiscordant couples with viral suppression have so far only reported follow-up data for 330 couple-years when condoms were not being used. Data are even more limited for anal sex in men who have sex with men. Additional data on the effectiveness of ART as prevention when practicing condom-less sex is urgently needed.

Background Data from randomized trials on the development of anaemia after interruption of therapy are not well-described. Methods A total of 2,248 patients from the SMART study were included. We used Cox proportional hazards models to investigate development of new (≤12 mg/dl for females and ≤14 mg/dl for males) or worsening (≤8 mg/dl if anaemic at randomization) anaemia and Poisson regression analyses to explore the relationship between anaemia and the development of AIDS, death or non-AIDS events. Results Overall, 759 patients developed new or worsening anaemia: 420/1,106 (38.0%) in the drug conservation (DC) arm and 339/1127 (30.1%) in the viral suppression (VS) arm ( PConclusions Patients who interrupted combination anti-retroviral therapy had a higher risk of new or worsening anaemia. Anaemic patients had a higher incidence of AIDS, non-AIDS defining events or deaths, possibly due to deteriorating health and subclinical disease.

Background This study evaluates the added benefit when estimating antiretroviral drug resistance of combining all available resistance test results in a cumulative genotype relative to using the latest genotype alone. Methods The prevalence of resistance and genotypic sensitivity scores (GSS) predicted by the latest and the cumulative genotype, together with virological outcomes after the latest genotype, were measured in treatment-experienced patients who underwent ≥2 resistance tests in 1999–2008. Results Comparing the latest with the cumulative genotype in 227 patients, 4 (1.7%) versus 0 (0.0%) showed no major resistance mutations, whereas 74 (32.6%) versus 46 (20.3%), 88 (38.8%) versus 76 (33.5%) and 61 (26.9%) versus 105 (46.3%) showed single-class, dual-class and triple-class resistance mutations, respectively. The median (IQR) number of fully or partially active drugs was 6 (5–6) versus 5 (4–6) for the nucleoside/nucleotide reverse transcriptase inhibitors, 3 (1–3) versus 1 (1–3) for the non-nucleoside reverse transcriptase inhibitors and 7 (7–7) versus 7 (7–7) for the protease inhibitors, respectively. Among 163 patients who started a new regimen after the latest genotype, both the latest and the cumulative GSS were predictive of early (≤24 weeks) virological responses. The GSS decreased by median 1 unit (IQR 0.5–1.0) in the cumulative genotype and larger differences relative to the latest genotype corresponded to smaller decreases in viral load. Conclusions The cumulative genotype offers a more comprehensive evaluation of the burden of resistance. This approach can guide small but appreciable improvements in the selection of antiretroviral regimens for treatment-experienced patients.

In HIV type-1-infected patients starting highly active antiretroviral therapy (HAART), the prognostic value of haemoglobin when starting HAART, and of changes in haemoglobin levels, are not well defined.We combined data from 10 prospective studies of 12,100 previously untreated individuals (25% women). A total of 4,222 patients (35%) were anaemic: 131 patients (1.1%) had severe (8.0 g/dl), 1,120 (9%) had moderate (male 8.0-11.0 g/dl and female 8.0-10.0 g/dl) and 2,971 (25%) had mild (male 11.0-13.0 g/ dl and female 10.0-12.0 g/dl) anaemia. We separately analysed progression to AIDS or death from baseline and from 6 months using Weibull models, adjusting for CD4+ T-cell count, age, sex and other variables.During 48,420 person-years of follow-up 1,448 patients developed at least one AIDS event and 857 patients died. Anaemia at baseline was independently associated with higher mortality: the adjusted hazard ratio (95% confidence interval) for mild anaemia was 1.42 (1.17-1.73), for moderate anaemia 2.56 (2.07-3.18) and for severe anaemia 5.26 (3.55-7.81). Corresponding figures for progression to AIDS were 1.60 (1.37-1.86), 2.00 (1.66-2.40) and 2.24 (1.46-3.42). At 6 months the prevalence of anaemia declined to 26%. Baseline anaemia continued to predict mortality (and to a lesser extent progression to AIDS) in patients with normal haemoglobin or mild anaemia at 6 months.Anaemia at the start of HAART is an important factor for short- and long-term prognosis, including in patients whose haemoglobin levels improved or normalized during the first 6 months of HAART.

Background We aimed to investigate the long-term virological outcomes of a cohort initially showing good responses to first-line highly active antiretroviral therapy (HAART) with no evidence of virological failure during the first year after achieving viral load (VL) undetectability (Methods Virological failure was defined as a confirmed VL>400 copies/ml or a single VL>400 copies/ml followed by a treatment change or end of follow-up. Risk factors for low-level VL rebound (50–400 copies/ml) in the first year after achieving undetectability and for virological failure during subsequent follow-up were investigated by logistic and Poisson regression. Results In the first year after achieving VL undetectability, 354/1,386 (25.5%) patients experienced low-level VL rebound, the remaining patients maintained consistent undetectability. Low-level rebound occurred less commonly with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART than with other regimens ( P=0.01). Over median 2.2 (range 0.0–7.4) years of subsequent follow-up, 86 (6.2%) patients experienced virological failure, corresponding to 2.30 failures per 100 person-years (95% confidence interval [CI] 1.82–2.79). Independent predictors of virological failure included low-level rebound during the first year after achieving undetectability relative to consistent undetectability (rate ratio [RR] 2.18, 95% CI 1.15–4.10), female gender (RR 1.79, 95% CI 1.12–2.85) and receiving a ritonavir-boosted protease inhibitor (PI/r) relative to NNRTI-based HAART (RR 1.88, 95% CI 1.02–3.46). Conclusions Patients on first-line HAART who maintain consistent VL undetectability for 1 year have a low risk of subsequent virological failure. A subset might benefit from targeted interventions, including women and patients on PI/r-based HAART.

BackgroundThe SMART trial found a raised risk of cardiovascular disease (CVD) events in patients undergoing CD4+T cell-count guided intermittent antiretroviral therapy (ART) compared with patients on continuous ART. Exploratory analyses were performed to better understand the reasons for this observation.MethodsA total of 5,472 patients with CD4+T-cell counts >350 cells/mm3were recruited and randomized to either continuous ART (the viral suppression arm; VS) or CD4+T-cell count-guided use of ART (the drug conservation arm; DC).ResultsMajor CVD events developed in 79 patients. The hazard ratio (HR) for risk of CVD events for DC versus VS was 1.57 (95% confidence interval 1.00–2.46; P=0.05). There was no evidence that being off ART or a higher current HIV viral load were associated with increased CVD risk. Total cholesterol and low-density lipoprotein cholesterol were reduced as a result of ART interruption in DC patients but so was high-density lipoprotein (HDL) cholesterol, leading to a net unfavourable change in the total/HDL cholesterol ratio.ConclusionsReasons for the higher risk of CVD for DC compared with VS patients remain unclear. There was no clear evidence to suggest that ART interruption per se or a higher HIV viral load were associated with an increased CVD risk in the DC group. Lipid changes were less favourable among DC compared with VS patients, which could offer a partial explanation.

The benefit of transient combination antiretroviral treatment (CART) during acute HIV infection is uncertain. We used the seroconverter database CASCADE to provide a historical comparison for the Quest trial, in which 79 subjects with acute HIV infection received CART for an average of 2.6 years, and 17.7% (95% confidence interval [CI]: 10.9-27.6) fulfilled the primary endpoint of VLor =1,000 copies/ml 24 weeks after CART discontinuation.We estimated the prevalence of VLor =1,000 copies/ml three years after seroconversion and prior to any ART among 385 sexually infected subjects in CASCADE who seroconverted between 1988 and 1996. We conducted a pre-specified comparison with the recently published Quest results, and considered potential biases.The prevalence of VLor =1,000 copies/ml at year three in CASCADE was 10.1% (95% CI: 7.5-13.5) (absolute difference compared to 17.7% in Quest: 7.6%; 95% CI: -0.1-17.8; P=0.053). In CASCADE, VLor =1,000 copies/ml was less common among homosexual and heterosexual men compared with women (8.5%, 7.3% and 17.6% respectively) and in subjects with symptomatic infection compared with those without (6.2% and 12.6%, respectively). As Quest had a much greater proportion of symptomatic subjects than CASCADE, any true difference in VL might be underestimated. Therefore this comparison suggests that transient CART in acute infection might result in a modest increase in the probability of low VL subsequently. However, several factors mitigate this conclusion. First, this historical comparison might be subject to other unmeasured confounders. Second, a comparison of median VL at the same time point was not significant (4.02 copies/ml and 4.20 copies/ml in Quest and CASCADE, respectively; P=0.55). Finally, additional analysis suggested that the observed difference in low VL at year three would be consistent with an immediate effect of CART only - a delay of usual VL decline without additional benefit.A small but significant proportion of seroconverters have low VL without ART. Transient CART in acute infection might increase the probability of low VL after treatment discontinuation, but such an effect is likely to be modest, and might represent a delay of natural history rather than a long-term therapeutic benefit.

It has been suggested that a lower pre-highly active antiretroviral therapy (HAART) CD4 count nadir may lead to a greater risk of experiencing HAART-related toxicity. We investigated the relationship between the pre-HAART CD4 count nadir, HAART and the occurrence of laboratory-defined toxicities.Previously antiretroviral-naive individuals starting HAART at the Royal Free Hospital, London, UK, were included. Drug discontinuation, increases in total cholesterol (by1 mmol/l), alanine aspartate transferase/ alanine aminotransferase (AST/ALT) (by2.5 times the upper limit of normal), bilirubin (by2.5 times the upper limit of normal), triglycerides (by1 mmol/l) and decreases in haemoglobin (by2 g/dl) were assessed.377/847 (45%) individuals starting HAART stopped at least one antiretroviral within the first 48 weeks. Lower CD4 nadirs were not associated with a greater rate of discontinuing antiretrovirals (adjusted hazard ratio (HR)=1.04 per 100 cells/mm3 higher; 95% confidence intervals (CI) 0.99 - 1.10; P = 0.15). 70/297 (24%), 39/192 (20%) and 73/358 (20%) with a CD4 cell nadir of 0-100, 100-200 and 200+ cells/mm3, respectively, stopped for toxicity reasons; 11/297 (4%), 5/192 (3%) and 3/358 (11%) stopped for reasons of insufficient efficacy; 63/297 (21%), 33/192 (17%) and 80/358 (22%) stopped for other reasons (P = 0.1). Reasons for stopping were similar between CD4 nadir groups. Lower CD4 nadirs were not associated with an increased risk of hypercholesterolaemia, anaemia, hypertriglyceridaemia or increases in AST/ALT but were associated with increased incidence of hyperbilirubinaemia (HR=0.67 per 100 cells/mm3 higher; 95% CI 0.49-0.92; P = 0.01).Lower CD4 nadirs were not found to be associated either with discontinuing an antiretroviral or with a higher risk of toxicity, except for an increased risk of experiencing an increase in bilirubin levels.

Objectives To assess the rate of change in viral load and CD4 count over time in HIV-infected patients experiencing virological failure on a HAART regimen. Design Study population included patients from EuroSIDA, a large, multicentre, observational study enrolling HIV-infected patients across Europe. Methods Median change in viral load and CD4 count per month were estimated using the viral load and CD4 measurements obtained over a 12-month period after confirmed virological failure between 3 and 4 log10 copies/ml in a population of 488 HIV-infected patients who were left on a failing HAART regimen. Results The estimated median viral load change in our study population was 0.024 log10 copies/ml per month, statistically different from 0 (P=0.0001). In 20.9% of the patients studied viral load showed a tendency to decrease, in 47.8% showed a tendency to increase by a positive rate no higher than 0.04 log10 copies/ml per month and in the remaining 31.3% showed a tendency to increase by a rate greater than 0.04 log10 copies/ml per month. On average, CD4 counts were estimated to remain stable (decrease at a slow rate of about –0.53 cells/μl per month). Conclusions In patients that remained on a stable, but virologically failing HAART regimen (with viral load ranging 1000–10000 copies/ml), the viral load over the ensuing 12-month period increased at a relatively slow rate. In contrast, the CD4 count remained stable, possibly because of partial but sustained viral suppression below the viral load natural set-point. The time-course of selecting more replication-competent virus in patients with virological failure remains to be fully clarified.

To compare two analytic approaches to assess the virological effect of HAART according to the intention-to-treat (ITT) principle.Data from 2318 patients enrolled in 10 randomised clinical trials (RCTs) and from 3091 patients followed in an observation cohort (EuroSIDA) starting their first HAART regimen.Two classifications of defining virological response 48 weeks after starting the therapy to be evaluated were compared: 1) only patients remaining on the therapy and having a plasma viral load (pVL) below a given cut-off level at week 48 were classified as responders (ITT/s=f); and 2) patients with a pVL below a given cut-off at week 48 whether they remained on initial assigned therapy or switched therapy were responders (ITT/s incl). In both analyses, patients with missing data at week 48 were classified as failures (i.e., non-responders).According to ITT/s=f, 22-70% of the patients starting a HAART regimen in a RCT experienced a virological response at week 48. Only two RCTs had complete follow-up data (n=424): between 29 and 62% achieved a virological response at week 48 in the six treatment arms evaluated in the studies according to ITT/s=f, and 41-72% according to ITT/s incl. Among those who discontinued the therapy to be evaluated in these two trials, 13-45% (cohort: 39-74%) subsequently experienced a virological response at week 48. The subsequent response rates were associated with the reason for discontinuation (toxicity versus confirmed virological failure: 63 vs 33%), varied largely across regimens and were not associated with the discontinuation rate.Discontinuation of follow-up at switch from the therapy to be evaluated remains common in antiretroviral treatment trials, but leads to an imprecise and incomplete assessment of the intrinsic effect of a given regimen. Complete follow-up of all patients should be encouraged strongly as this will allow for several complementary analytic approaches and a focus on optimal treatment strategies rather than specific regimens.

Objective To assess the relationship between viral susceptibility at baseline and virological response in human immunodeficiency virus (HIV)–infected patients treated with multi-drug salvage regimens after multiple previous treatment failures. Design Retrospective analysis of 50 patients from the Frankfurt HIV cohort who had received treatment with a minimum of six drugs, and for whom a sample for baseline viral phenotyping was available. Methods: Viral drug susceptibility was measured retrospectively from stored samples using the Antivirogram, a recombinant virus assay based method. Virological response was defined as a viral load of Results At baseline, drug resistance was extensive: 96% of patients had viruses resistant to at least one drug class and 32% had viruses resistant to all three drug classes. In the DAF analysis, 39 patients experienced virological failure. In the DAC analysis, eight were censored and 31 patients experienced virological failure. In multivariate models that adjust for baseline viral load, the number of new drugs and total phenotypic sensitivity scores, the baseline viral load and phenotypic sensitivity score remained significantly associated with virological outcome, whereas in those adjusted for baseline viral load, the number of new drugs, NRTI phenotypic sensitivity score and PI phenotypic sensitivity score, only the latter remained significantly associated with virological outcome. Both the DAF and DAC analyses produced similar results. In all models used, virological failure was shown to be significantly associated with baseline viral load and phenotypic sensitivity score. Conclusions In this retrospective analysis based on a small number of patients, viral drug susceptibility at baseline was strongly associated with virological outcome at 24 weeks, independent of covariates such as baseline viral load and treatment history. Baseline viral load also maintained a significant, independent association with virological outcome in most models.