Predictors of CD4(+) T-cell counts of HIV type 1-infected persons after virologic failure of all 3 original antiretroviral drug classes.

BACKGROUND: Low CD4(+) T-cell counts are the main factor leading to clinical progression in human immunodeficiency virus type 1 (HIV-1) infection. We aimed to investigate factors affecting CD4(+) T-cell counts after triple-class virological failure. METHODS: We included individuals from the COHERE database who started antiretroviral therapy from 1998 onward and who experienced triple-class virological failure. CD4(+) T-cell counts obtained after triple-class virologic failure were analyzed using generalized estimating equations. RESULTS: The analyses included 2424 individuals with a total of 23 922 CD4(+) T-cell count measurements. In adjusted models (excluding current viral load and year), CD4(+) T-cell counts were higher with regimens that included boosted protease inhibitors (increase, 22 cells/µL [95% confidence interval {CI}, 3.9-41]; P = .017) or drugs from the new classes (increase, 39 cells/µL [95% CI, 15-62]; P = .001), compared with nonnucleoside reverse-transcriptase inhibitor-based regimens. These associations disappeared when current viral load and/or calendar year were included. Compared with viral levels of <2.5 log(10) copies/mL, levels of 2.5-3.5, 3.5-4.5, 4.5-5.5, and >5.5 log(10) copies/mL were associated with CD4(+) T-cell count decreases of 51, 84, 137, and 186 cells/µL, respectively (P < .001). CONCLUSIONS: The approximately linear inverse relationship between log(10) viral load and CD4(+) T-cell count indicates that there are likely immunologic benefits from lowering viral load even by modest amounts that do not lead to undetectable viral loads. This is important for patients with low CD4(+) T-cell counts and few drug options.

Risk factors and outcomes for late presentation for HIV-positive persons in Europe: results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE).

BACKGROUND: Few studies have monitored late presentation (LP) of HIV infection over the European continent, including Eastern Europe. Study objectives were to explore the impact of LP on AIDS and mortality. METHODS AND FINDINGS: LP was defined in Collaboration of Observational HIV Epidemiological Research Europe (COHERE) as HIV diagnosis with a CD4 count <350/mm(3) or an AIDS diagnosis within 6 months of HIV diagnosis among persons presenting for care between 1 January 2000 and 30 June 2011. Logistic regression was used to identify factors associated with LP and Poisson regression to explore the impact on AIDS/death. 84,524 individuals from 23 cohorts in 35 countries contributed data; 45,488 were LP (53.8%). LP was highest in heterosexual males (66.1%), Southern European countries (57.0%), and persons originating from Africa (65.1%). LP decreased from 57.3% in 2000 to 51.7% in 2010/2011 (adjusted odds ratio [aOR] 0.96; 95% CI 0.95-0.97). LP decreased over time in both Central and Northern Europe among homosexual men, and male and female heterosexuals, but increased over time for female heterosexuals and male intravenous drug users (IDUs) from Southern Europe and in male and female IDUs from Eastern Europe. 8,187 AIDS/deaths occurred during 327,003 person-years of follow-up. In the first year after HIV diagnosis, LP was associated with over a 13-fold increased incidence of AIDS/death in Southern Europe (adjusted incidence rate ratio [aIRR] 13.02; 95% CI 8.19-20.70) and over a 6-fold increased rate in Eastern Europe (aIRR 6.64; 95% CI 3.55-12.43). CONCLUSIONS: LP has decreased over time across Europe, but remains a significant issue in the region in all HIV exposure groups. LP increased in male IDUs and female heterosexuals from Southern Europe and IDUs in Eastern Europe. LP was associated with an increased rate of AIDS/deaths, particularly in the first year after HIV diagnosis, with significant variation across Europe. Earlier and more widespread testing, timely referrals after testing positive, and improved retention in care strategies are required to further reduce the incidence of LP.

Trends in virological and clinical outcomes in individuals with HIV-1 infection and virological failure of drugs from three antiretroviral drug classes: a cohort study.

BACKGROUND: Limited treatment options have been available for people with HIV who have had virological failure of the three original classes of HIV antiretroviral drugs-so-called triple-class virological failure (TCVF). However, introduction of new drugs and drug classes might have improved outcomes. We aimed to assess trends in virological and clinical outcomes for individuals with TCVF in 2000-09. METHODS: In our cohort study, we analysed data for adults starting antiretroviral therapy from 1998 in cohorts participating in the PLATO II project, which is part of COHERE, a collaboration of European cohorts. TCVF was defined as virological failure to at least two nucleoside reverse transcriptase inhibitors, one non-nucleoside reverse-transcriptase inhibitor, and one ritonavir-boosted protease inhibitor, with virological failure of a drug defined as one viral-load measurement of greater than 500 copies per mL after at least 4 months of continuous use. We used multivariable generalised estimating equation logistic models and Poisson regression models to study trends in virological suppression and incidence of AIDS or death after TCVF. We adjusted for sex, transmission group, age, AIDS status, CD4 cell count, plasma viral loads at TCVF, achievement of virological response (<50 copies per mL), and number of drug failures before TCVF. FINDINGS: 28 of 33 cohorts in COHERE contributed data to the PLATO II project, of which four had no participants eligible for inclusion in this study. 2476 (3%) of 91 764 participants from the remaining 24 cohorts had TCVF and at least one viral load measurement in 2000-09. The proportion of patients with virological response after TCVF increased from 19·5% in 2000 to 57·9% in 2009 (adjusted p<0·0001). Incidence of AIDS decreased from 7·7 per 100 person-years in 2000-02 to 2·3 in 2008 and 1·2 in 2009 (adjusted p<0·0001). Mortality decreased from 4·0 per 100 person-years between 2000 and 2002 to 1·9 in 2007 and 1·4 in 2008 (unadjusted p=0·023), but the trend was not significant after adjustment (p=0·22). INTERPRETATION: A substantial improvement in viral load suppression and accompanying decrease in the rates of AIDS in people after extensive failure to drugs from the three original antiretroviral classes during 2000-09 was probably mainly driven by availability of newer drugs with better tolerability and ease of use and small cross-resistance profiles, suggesting the public health benefit of the introduction of new drugs.

Calendar time trends in the incidence and prevalence of triple-class virologic failure in antiretroviral drug-experienced people with HIV in Europe.

BACKGROUND: Despite the increasing success of antiretroviral therapy (ART), virologic failure of the 3 original classes [triple-class virologic failure, (TCVF)] still develops in a small minority of patients who started therapy in the triple combination ART era. Trends in the incidence and prevalence of TCVF over calendar time have not been fully characterised in recent years. METHODS: Calendar time trends in the incidence and prevalence of TCVF from 2000 to 2009 were assessed in patients who started ART from January 1, 1998, and were followed within the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). RESULTS: Of 91,764 patients followed for a median (interquartile range) of 4.1 (2.0-7.1) years, 2722 (3.0%) developed TCVF. The incidence of TCVF increased from 3.9 per 1000 person-years of follow-up [95% confidence interval (CI): 3.7 to 4.1] in 2000 to 8.8 per 1000 person-years of follow-up (95% CI: 8.5 to 9.0) in 2005, but then declined to 5.8 per 1000 person-years of follow-up (95% CI: 5.6 to 6.1) by 2009. The prevalence of TCVF was 0.3% (95% CI: 0.27% to 0.42%) at December 31, 2000, and then increased to 2.4% (95% CI: 2.24% to 2.50%) by the end of 2005. However, since 2005, TCVF prevalence seems to have stabilized and has remained below 3%. CONCLUSIONS: The prevalence of TCVF in people who started ART after 1998 has stabilized since around 2005, which most likely results from the decline in incidence of TCVF from this date. The introduction of improved regimens and better overall HIV care is likely to have contributed to these trends. Despite this progress, calendar trends should continue to be monitored in the long term.

Triple-class virologic failure in HIV-infected patients undergoing antiretroviral therapy for up to 10 years.

BACKGROUND: Life expectancy of people with human immunodeficiency virus (HIV) is now estimated to approach that of the general population in some successfully treated subgroups. However, to attain these life expectancies, viral suppression must be maintained for decades. METHODS: We studied the rate of triple-class virologic failure (TCVF) in patients within the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) who started antiretroviral therapy (ART) that included a nonnucleoside reverse-transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r) from 1998 onwards. We also focused on TCVF in patients who started a PI/r-containing regimen after a first-line NNRTI-containing regimen failed. RESULTS: Of 45 937 patients followed up for a median (interquartile range) of 3.0 (1.5-5.0) years, 980 developed TCVF (2.1%). By 5 and 9 years after starting ART, an estimated 3.4% (95% confidence interval [CI], 3.1%-3.6%) and 8.6% (95% CI, 7.5%-9.8%) of patients, respectively, had developed TCVF. The incidence of TCVF rose during the first 3 to 4 years on ART but plateaued thereafter. There was no significant difference in the risk of TCVF according to whether the initial regimen was NNRTI or PI/r based (P = .11). By 5 years after starting a PI/r regimen as second-line therapy, 46% of patients had developed TCVF. CONCLUSIONS: The rate of virologic failure of the 3 original drug classes is low, but not negligible, and does not appear to diminish over time from starting ART. If this trend continues, many patients are likely to need newer drugs to maintain viral suppression. The rate of TCVF from the start of a PI/r regimen after NNRTI failure provides a comparator for studies of response to second-line regimens in resource-limited settings.