Search

Summary Background In lower-income countries, WHO recommends a population-based approach to antiretroviral treatment with standardised regimens and clinical decision making based on clinical status and, where available CD4 cell count, rather than viral load. Our aim was to study the potential consequences of such monitoring strategies, especially in terms of survival and resistance development. Methods A validated computer simulation model of HIV infection and the effect of antiretroviral therapy was used to compare survival, use of second-line regimens, and development of resistance that result from different strategies—based on viral load, CD4 cell count, or clinical observation alone—for determining when to switch people starting antiretroviral treatment with the WHO-recommended first-line regimen of stavudine, lamivudine, and nevirapine to second-line antiretroviral treatment. Findings Over 5 years, the predicted proportion of potential life-years survived was 83% with viral load monitoring (switch when viral load >500 copies per mL), 82% with CD4 cell count monitoring (switch at 50% drop from peak), and 82% with clinical monitoring (switch when two new WHO stage 3 events or a WHO stage 4 event occur). Corresponding values over 20 years were 67%, 64%, and 64%. Findings were robust to variations in model specification in extensive univariable and multivariable sensitivity analyses. Although survival was slightly longer with viral load monitoring, this strategy was not the most cost effective. Interpretation For patients on the first-line regimen of stavudine, lamivudine, and nevirapine the benefits of viral load or CD4 cell count monitoring over clinical monitoring alone are modest. Development of cheap and robust versions of these assays is important, but widening access to antiretrovirals—with or without laboratory monitoring—is currently the highest priority. Funding None.

Background We examined whether the initial virological and immunological response to highly active antiretroviral treatment (HAART) is prognostic in patients with HIV-1 who start HAART. Methods We analysed 13 cohort studies from Europe and North America including 9323 adult treatment-naive patients who were starting HAART with a combination of at least three drugs. We modelled clinical progression from month 6 after starting HAART, taking into account CD4 count and HIV-1 RNA measured at baseline and 6 months. Findings During 13408 years of follow-up 152 patients died and 874 developed AIDS or died. Compared with patients who had a 6-month CD4 count of fewer than 25 cells/microL, adjusted hazard ratios for AIDS or death were 0.55 (95%CI 0.32-0.96) for 25-49 cells/microL, 0.62 (0.40-0.96) for 50-99 cells/microL, 0.42 (0.28-0.64) for 100-199 cells/microL, 0.25 (0.16-0.38) for 200-349 cells/microL, and 0.18 (0.11-0.29) for 350 or more cells/microL at 6 months. Compared with patients who had a 6-month HIV-1 RNA of 100000 copies/mL or greater, adjusted hazard ratios for AIDS or death were 0.59 (0.41-0.86) for 10000-99999 copies/mL, 0.42 (0.29-0.61) for 500-9999 copies/mL, and 0.29 (0.21-0.39) for 6-month HIV-1 RNA of 500 copies/mL or fewer. Baseline CD4 and HIV-1 RNA were not associated with progression after controlling for 6-month concentrations. The probability of progression at 3 years ranged from 2.4% in the patients in the lowest-risk stratum to 83% in patients in the highest-risk stratum. Interpretation At 6 months after starting HAART, the current CD4 cell count and viral load, but not values at baseline, are strongly associated with subsequent disease progression. Our findings should inform guidelines on when to modify HAART.

Summary Background Insufficient data are available from single cohort studies to allow estimation of the prognosis of HIV-1 infected, treatment-naive patients who start highly active antiretroviral therapy (HAART). The ART Cohort Collaboration, which includes 13 cohort studies from Europe and North America, was established to fill this knowledge gap. Methods We analysed data on 12 574 adult patients starting HAART with a combination of at least three drugs. Data were analysed by intention-to-continue-treatment, ignoring treatment changes and interruptions. We considered progression to a combined endpoint of a new AIDS-defining disease or death, and to death alone. The prognostic model that generalised best was a Weibull model, stratified by baseline CD4 cell count and transmission group. Findings During 24 310 person-years of follow up, 1094 patients developed AIDS or died and 344 patients died. Baseline CD4 cell count was strongly associated with the probability of progression to AIDS or death: compared with patients starting HAART with less than 50 CD4 cells/μL, adjusted hazard ratios were 0·74 (95% CI 0·62–0·89) for 50–99 cells/μL, 0·52 (0·44–0·63) for 100–199 cells/μL, 0·24 (0·20–0·30) for 200–349 cells/μL, and 0·18 (0·14–0·22) for 350 or more CD4 cells/μL. Baseline HIV-1 viral load was associated with a higher probability of progression only if 100 000 copies/mL or above. Other independent predictors of poorer outcome were advanced age, infection through injection-drug use, and a previous diagnosis of AIDS. The probability of progression to AIDS or death at 3 years ranged from 3·4% (2·8–4·1) in patients in the lowest-risk stratum for each prognostic variable, to 50% (43–58) in patients in the highest-risk strata. Interpretation The CD4 cell count at initiation was the dominant prognostic factor in patients starting HAART. Our findings have important implications for clinical management and should be taken into account in future treatment guidelines.

Summary Background Risk factors for lipodystrophy in patients infected with HIV-1 treated with highly active antiretroviral therapy (HAART) containing HIV-1 protease inhibitors are poorly understood. We aimed to identify the risk factors for lipodystrophy in antiretroviral-naive HIV-1-infected adults on HAART. Methods Moderate or severe body-fat changes were clinically assessed and categorised as subcutaneous lipoatrophy, central obesity, or both, in all consecutive antiretroviral-naive HIV-1-infected adults who began HAART with two nucleoside reverse transcriptase inhibitors plus at least one protease inhibitor from October, 1996, to September, 1999. A person-years analysis was used to calculate the incidence of types of lipodystrophy, and Cox proportional hazards models were used to describe the univariate and multivariate factors associated with progression to any lipodystrophy. Findings After a median follow-up of 18 months, 85 (17%) of the 494 patients developed some type of lipodystrophy. The incidences of any lipodystrophy, lipodystrophy with subcutaneous lipoatrophy, and lipodystrophy with central obesity were 11·7 (95% CI 9·2–14·2), 9·2 (7·0–11·4), and 7·7 (5·7–9·7) per 100 patient-years. An increased risk for any lipodystrophy was found among women as compared with men (relative hazard 1·87 [1·07–3·28]), heterosexuals (2·86 [1·50–5·48]), and homosexuals (2·17 [1·07–4·42]) as compared with intravenous drug users, with increasing age (1·33 per 10 years older [1·08–1·62]), and with the duration of exposure to antiretroviral therapy (1·57 per 6 months extra [1·30–1·88]) but not with any individual antiretroviral agent. The factors associated with an increased risk for lipodystrophy with subcutaneous lipoatrophy or lipodystrophy with central obesity were very similar to those associated with any lipodystrophy. The duration of indinavir use may represent an additional contribution for the development of lipodystrophy with central obesity (1·26 per 6 months extra [0·99–1·60]); p=0·064). Interpretation Risk factors associated with development of any lipodystrophy, lipodystrophy with subcutaneous lipoatrophy, and lipodystrophy with central obesity in patients infected with HIV-1 who were receiving HAART containing protease inhibitors are multifactorial and overlapping, and cannot be exclusively ascribed to the duration of exposure to an particular antiretroviral agent.

Summary Background We used data from Europe, North America, and Australia to assess the effect of exposure category on the AIDS incubation period and HIV-1 survival and whether the effect of age at seroconversion varies with exposure category and with time since seroconversion. Methods 38 studies of HIV-1-infected individuals whose dates of seroconversion could be reliably estimated were included in the analysis. Individual data on 13 030 HIV-1-infected individuals from 15 countries were collated, checked, and analysed centrally. We calculated estimates of mortality and AIDS incidence rates and estimated the proportions of individuals surviving and developing AIDS at each year after seroconversion from the numbers of observed deaths or cases of AIDS and the corresponding person-years at risk. Analyses were adjusted for age at seroconversion, time since seroconversion, and other factors as appropriate. Findings Mortality and AIDS incidence increased strongly with time since seroconversion and age at seroconversion. Median survival varied from 12·5 years (95% Cl 12·1–12·9) for those aged 15–24 years at seroconversion to 7·9 years (7·4–8·5) for those aged 45–54 years at seroconversion, whereas for development of AIDS the corresponding values were 11·0 years (10·7–11·7) and 7·7 years (7·1–8·6). There was no appreciable effect of exposure category on survival. For AIDS incidence, the exposure category effect that we noted was explained by the high incidence of Kaposi's sarcoma in those infected through sex between men. We estimated that among people aged 25–29 years at seroconversion 90% (89–91) and 60% (57–62) survived to 5 years and 10 years, respectively, after seroconversion, whereas 13% (12–15) and 46% (44–49), respectively, developed AIDS (excluding Kaposi's sarcoma). Interpretation Before widespread use of highly-active antiretroviral therapy (before 1996), time since seroconversion and age at seroconversion were the major determinants of survival and development of AIDS in Europe, North America, and Australia.

Summary Background Highly active antiretroviral therapy (HAART) has improved rates of CD4-lymphocyte recovery and decreased the incidence of HIV-1-related morbidity and mortality. We assessed whether prophylaxis against Pneumocystis carinii pneumonia (PCP) can be safely discontinued after HAART is startedt Methods We investigated 7333 HIV-1-infected patients already enrolled in EuroSIDA, a continuing prospective observational cohort study in 52 centres across Europe and Israel. We did a person-years analysis of the rate of discontinuation of PCP prophylaxis and of the incidence of PCP after the introduction of HAART into clinical practice from July, 1996 Findings The rate of discontinuation of primary and secondary PCP prophylaxis increased up to 21–9 discontinuations per 100 person-years of follow-up after March, 1998. 378 patients discontinued primary (319) or secondary (59) prophylaxis a median of 10 months after starting HAART. At discontinuation for primary and secondary prophylaxis, respectively, the median CD4-lymphocyte counts were 274 cells/μL and 270 cells/μL, the median plasma HIV-1 RNA load 500 copies/mL, and the median lowest recorded CD4-lymphocyte counts 123 cells/μL and 60 cells/μL. During 247 person-years of follow-up, no patient developed PCP (incidence density 0 [95% Cl 0-1·5]). Interpretation The risk of PCP after stopping primary prophylaxis, especially in patients on HAART with a rise in CD4-lymphocyte count to more than 200 cells/μL, is sufficiently low to warrant discontinuation of primary PCP prophylaxis. Longer follow-up is needed to confirm a similarly low risk for stopping secondary PCP prophylaxis.

Background Suppression of plasma HIV viral load to less than 50 copies per mL is associated with durable clinical and immunological benefits and is the recommended goal of antiretroviral therapy (ART). Currently available viral load assays can detect HIV RNA below this threshold but the importance of low-level detection is unclear. We aimed to determine whether HIV RNA detection below 50 copies per mL is associated with an increased risk of virological rebound in ART-treated patients. Methods 1247 HIV-positive patients on ART with viral load less than 50 copies per mL at a single arbitrary timepoint as measured by RealTi me PCR (Abbott, Maidenhead, UK) were stratified by the clinically unreported viral load into three groups: 40–49 copies per mL (RNA40–49), less than 40 copies per mL but not quantifiable (RNA+), and not detected (RNA−). Virological outcomes over the following 12 months were analysed. Time to viral load rebound according to baseline viral load category was assessed and the factors associated with rebound were identified in a Cox proportional hazards model incorporating baseline viral load, clinical and demographic data, and adherence levels. Findings Over 12 months of follow-up the proportion of patients experiencing viral load rebound of more than 50 copies per ml in the RNA40–49, RNA+, and RNA–groups were 34·2% (82/240), 11·3% (57/507), and 4% (20/500), respectively. For viral rebound of more than 400 copies per mL the proportions were 13% (31/240), 3·8% (19/507), and 1·2% (6/500), respectively. After multivariate adjustment, the hazard ratio for rebound of more than 400 copies per mL was 6·91 (95% CI 2·90–16·47, p Interpretation In ART-treated HIV-positive patients, detection of viral load between 40 and 49 copies per mL and less than 40 copies per mL (as measured by RealTi me PCR) is associated with an increased risk of virological failure. The currently recommended goal of ART of 50 copies per mL might be suboptimal and might need to be revised to a lower cut-off. Funding Royal Free Hospital NHS Trust, European AIDS Treatment Network.