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Background Incomplete antiretroviral therapy (ART) adherence has been linked to deleterious immunologic, inflammatory, and clinical consequences, even among virally suppressed ( Methods We estimated the reduction in the risk of SNAEs or death resulting from an increase in ART adherence by (1) applying existing data on the association between adherence with high residual inflammation/coagulopathy in virally suppressed PWH, and (2) using a Cox proportional hazards model derived from changes in plasma interleukin 6 (IL-6) and D-dimer from 3 randomized clinical trials. Comparatively, assuming 100% ART adherence in a PWH who achieves viral suppression, we estimated the number of persons in whom a decrease in adherence to Results Increasing ART adherence to 100% in PWH who are suppressed on ART despite imperfect adherence translated into a 6%–37% reduction in the risk of SNAEs or death. Comparatively, based on an anticipated 12% increase in IL-6, 254 and 165 PWH would need to decrease their adherence from 100% to Conclusions Modest gains in ART adherence could have clinical benefits beyond virologic suppression. Increasing ART adherence (eg, via an intervention or switch to long-acting ART) in PWH who remain virally suppressed despite incomplete adherence should be evaluated.

Background The public health impact of the coronavirus disease 2019 (COVID-19) pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. Methods Using a mathematical model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care. Results The impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R = 1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalization) could have much greater benefits, particularly in resource-poor settings facing large epidemics. Conclusions Advances in the treatment of COVID-19 to date have been focused on hospitalized-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.

Background In the 1980s debate intensified over whether there was a protective effect of high-density lipoprotein cholesterol (HDL-C) or an adverse effect of triglycerides on coronary heart disease (CHD) risk. In a 1991 paper reprinted in the IJE we suggested that the high degree of correlation between the two, together with plausible levels of measurement error, made it unlikely that conventional epidemiological approaches could contribute to causal understanding. The consensus that HDL-C was protective, popularly reified in the notion of ‘good cholesterol’, strengthened over subsequent years. Reviewing the biostatistical and epidemiological literature from before and after 1991 we suggest that within the observational epidemiology pantheon only Mendelian randomization studies—that began to appear at the same time as the initial negative randomized controlled trials—made a meaningful contribution. It is sobering to realize that many issues that appear suitable targets for epidemiological investigation are simply refractory to conventional approaches. The discipline should surely revisit this and other high-profile cases of consequential epidemiological failure—such as that with respect to vitamin E supplementation and CHD risk—rather than pass them over in silence.

International relations (IR) scholars commonly accept the sovereign state’s ubiquity today as the endpoint of a centuries-long process of modernization, spearheaded by European imperialism. Through this schema, European military superiority enabled Westerners to first impose themselves on non-European societies in the early modern period. The later spread of Western conceptions of national self-determination then compelled global convergence toward the sovereign state form after 1945. Conversely, I argue here that such accounts overstate the West’s margin of military superiority over non-Europeans throughout the age of empire. As a result, they also exaggerate European latitude in imposing their preferred institutional forms on conquered societies and mischaracterize the character of colonial modernity. Drawing inspiration from global history and harnessing illustrations from the Indian Ocean region, I argue that Western imperialism was critically mediated by Europeans’ alliances of convenience with indigenous partners. This dependence on local allies persisted throughout the colonial era as Western imperialists leveraged local institutions and conceptions of political legitimacy to perpetuate colonial rule. Acknowledging this reality forces us to critically revisit conventional narratives about the sovereign state system’s universalization, and to foreground hybridity over homogenization as global modernity’s master theme.

Effect estimates from randomized trials and observational studies might not be directly comparable because of differences in study design, other than randomization, and in data analysis. We propose a 3-step procedure to facilitate meaningful comparisons of effect estimates from randomized trials and observational studies: 1) harmonization of the study protocols (eligibility criteria, treatment strategies, outcome, start and end of follow-up, causal contrast) so that the studies target the same causal effect, 2) harmonization of the data analysis to estimate the causal effect, and 3) sensitivity analyses to investigate the impact of discrepancies that could not be accounted for in the harmonization process. To illustrate our approach, we compared estimates of the effect of immediate with deferred initiation of antiretroviral therapy in individuals positive for the human immunodeficiency virus from the Strategic Timing of Antiretroviral Therapy (START) randomized trial and the observational HIV-CAUSAL Collaboration.

International Relations theories generally hold that increased interaction between units in an international system produces convergence in their forms through military competition, institutional emulation, or normative socialization. In contrast, we argue that diverse international systems can endure despite increasing interaction. The early modern Indian Ocean international system hosted a variety of statist, corporate, and imperial polities. Diversity endured for three reasons. First, powerful foreign and local actors held differing maritime and land-oriented preferences for conquest, which created the potential for coexistence between unlike polities. Second, congruent European and Asian ideas of heteronomy facilitated durable polity diversity. Third, strategies of localization enhanced enmeshment. Convergence on common polity forms failed to occur despite the presence of a statist model during this period. Subsequently, a reconfigured form of diversity under colonial empires succeeded this order. Greater attention to past diverse systems coheres with recent calls to study history to better understand not only contemporary instances of international hierarchy, but also unbundled and shared sovereignty regimes

Background. We assessed factors associated with antiretroviral therapy (ART) adherence, including specific ART medications. Methods. The Strategies for Management of Antiretroviral Therapy study was an international antiretroviral therapy (ART) strategy trial that compared intermittent ART, using CD4+ T-cell count as a guide, to continuous ART. Adherence during the 7 days before each visit was measured using self-report. We defined high adherence as self-report of taking “all” pills for each prescribed ART medication; all other reports were defined as suboptimal adherence. Factors associated with adherence were assessed using logistic regression with generalized estimating equations. Results. Participants reported suboptimal adherence at 6016 of 35 695 study visits (17%). Factors independently associated with suboptimal adherence were black race, protease inhibitor–containing regimens, greater pill burden, higher maximum number of doses per day, and smoking. Factors independently associated with higher adherence were older age, higher education, region of residence, episodic treatment, higher latest (at the time of adherence) CD4+ T-cell count, and being prescribed concomitant drugs (ie, medications for comorbidities). Of specific drugs investigated, atazanavir, atazanavir/ritonavir, fosamprenavir, indinavir, indinavir/ritonavir, and lopinavir/ritonavir were associated with suboptimal adherence, and tenofovir disoproxil fumarate/emtricitabine was associated with higher adherence. Conclusions. In this, the largest analysis of ART adherence to date, some protease inhibitor–containing regimens and regimens with >1 dose per day were associated with suboptimal adherence.

Liver diseases are among the most frequent causes of non-AIDS–related deaths in human immunodeficiency virus (HIV)-positive persons [1–4]. Most deaths result from hepatitis C (HCV) or hepatitis B virus (HBV) coinfections or alcohol use; little is known about other causes [5]. Results of 2 prospective observational cohorts suggest that prolonged exposure to antiretroviral therapy (ART) may increase the risk for fatal liver failure. The Data Collection on Adverse Events of Anti-HIV Drug (D:A:D) cohort, which includes many HCV-coinfected persons, found an increased rate of liver-related deaths per year of ART in multivariable analyses that were also adjusted for the latest CD4 cell counts [1]. The EuroSIDA observational cohort showed similar results [6]. The role of ART in liver-related mortality in patients without chronic viral hepatitis is less well defined. In the Swiss HIV Cohort Study (SHCS), elevated alanin aminotransferase (ALT; reported as adverse events to antiretrovirals), was associated with a higher mortality, independent of chronic hepatitis virus coinfections [7]. In contrast, mortality was not increased in participants with chronic ALT elevation and without viral hepatitis in another SHCS analysis; however, the observation period was shorter and the patient number smaller [8]. Recently, new hepatic syndromes related to ART have emerged in HIV-infected persons. Noncirrhotic portal hypertension, a potentially life-threatening liver disease, has been linked to didanosine use [9, 10]. In addition, steatosis and steatohepatitis are common in HIV-positive persons with and without chronic viral hepatitis [11, 12] and are associated with advanced liver fibrosis and cirrhosis [13]; ART as a risk factor has been discussed. The aims of this study were to (1) assess liver-related mortality in HIV-positive persons without chronic viral hepatitis in the D:A:D cohort and (2) provide comprehensive clinical details of these events. The role of ART in death was of particular interest.

Plasma human immunodeficiency virus type 1 (HIV-1) RNA suppression50 copies/mL is regarded as the optimal outcome of highly active antiretroviral therapy (HAART). Current viral load (VL) assays show increased sensitivity, but the significance of RNA detection50 copies/mL is unclear.This study investigated the virologic outcomes of 1247 patients with VL50 copies/mL at an arbitrary time point during HAART (= T0), according to whether the actual, unreported (T0)VL was 40-49 copies/mL, RNA detected40 copies/mL (RNA(+)), or RNA not detected (RNA(-)), as measured by the Abbott Real Time assay. Predictors of rebound50 and400 copies/mL over 12 months following T0 were analyzed with Cox proportional hazards models incorporating the (T0)VL and demographic and clinical data.Rebound rates50 copies/mL were 34.2% for (T0)VL 40-49 copies/mL, 11.3% for RNA(+), and 4.0% for RNA(-); rebound rates400 copies/mL were 13.0%, 3.8%, and 1.2%, respectively. The adjusted hazard ratios for rebound50 copies/mL were 4.67 (95% confidence interval, 2.91-7.47; P .0001) and 1.97 (1.25-3.11; P .0001) with (T0)VL 40-49 copies/mL and RNA(+), respectively, relative to RNA(-), and 6.91 (2.90-16.47; P .0001) and 2.88 (1.24-6.69; P .0001), respectively, for rebound400 copies/mL. The association was independent of adherence levels.In treated patients monitored by RealTime, a VL of 40-49 copies/mL and, to a lesser extent, RNA detection40 copies/mL predict rebound50 and400 copies/mL independently of other recognized determinants. The goal of HAART may need to be revised to a lower cutoff than 50 copies/mL.

Concerns have arisen about possible effects of protease inhibitors (PIs) on cardiac conductivity. We found no significant association between current or recent PI exposure and sudden death or nonhemorrhagic stroke (adjusted rate ratio, 1.22; 95% confidence interval, .95-1.57), whereas cumulative exposure to PIs was associated with an increased risk (adjusted rate ratio, 1.06 per year of exposure; 95% confidence interval, 1.01-1.11).

Background. Recent updates of human immunodeficiency virus (HIV) treatment guidelines have raised the CD4+ cell count thresholds for antiretroviral therapy initiation from 350 to 500 cells/mm(3) in the United States and from 200 to 350 cells/mm(3) in mid- and low-income countries. Robust data of time from HIV seroconversion to CD4+ cell counts of 200, 350, and 500 cells/mm(3) are lacking but are needed to inform health care planners of the likely impact and cost effectiveness of these and possible future changes in CD4+ cell count initiation threshold. Methods. Using Concerted Action on Seroconversion to AIDS and Death in Europe data from individuals with well-estimated dates of HIV seroconversion, we fitted mixed models on the square root of CD4+ cell counts measured before combined antiretroviral therapy (cART) initiation. Restricting analyses to adults (age >16 years), we predicted time between seroconversion and CD4+ cell count

Background. Robust long-term estimates of the risk of development of drug resistance are needed for human immunodeficiency virus (HIV)-infected patients starting combination antiretroviral therapy (cART) regimens currently used in routine clinical practice.Methods. We followed a large cohort of patients seen in 1 of 11 HIV clinics in the United Kingdom after starting cART with nucleoside reverse-transcriptase inhibitors and either a nonnucleoside reverse-transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r). Survival analysis was employed to estimate the incidence of virological failure and of detected drug resistance.Results. Seven thousand eight hundred ninety-one patients were included; 6448 (82%) started cART with an NNRTI and 1423 (17%) with a PI/r. The cumulative risk of virological failure by 8 years was 28%. The cumulative probabilities of detecting any mutation, >= 1 major nucleoside reverse-transcriptase inhibitor International AIDS Society-United States of America (IAS-USA) mutation, >= 1 major NNRTI IAS-USA mutation (in those starting an NNRTI), and >= 1 major PI IAS-USA mutation (in those starting a PI) were 17%, 14%, 15%, and 7%, respectively, by 8 years. The probability of detecting PI mutations in people who started PI/r-based regimens was lower than that of detecting NNRTI mutations in those starting NNRTI-based regimens (adjusted relative hazard, 0.36; 95% confidence interval, 0.26-0.50; P < .001). The risk of detecting nucleoside resistance did not vary according to whether an NNRTI or a PI/r was used in the regimen (adjusted relative hazard, 1.00; 95% confidence interval, 0.80-1.26; P = .98).Conclusions. In patients who started modern cART in clinical practice in the United Kingdom, virological failure by 8 years was relatively common and was paralleled by an appreciable risk of resistance detection, although the detection rate of class-specific resistance was lower for those who started a PI/r-based regimen.

BACKGROUND. The risk of myocardial infarction (MI) in patients with human immunodeficiency virus (HIV) infection has been assessed in 13 anti-HIV drugs in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. METHODS. Poisson regression models were adjusted for cardiovascular risk factors, cohort, calendar year, and use of other antiretroviral drugs and assessed the association between MI risk and cumulative (per year) or recent (current or in the past 6 months) use of antiretroviral drugs, with >30,000 person-years of exposure. RESULTS. Over 178,835 person-years, 580 patients developed MI. There were no associations between use of tenofovir, zalcitabine, zidovudine, stavudine, or lamivudine and MI risk. Recent exposure to abacavir or didanosine was associated with an increased risk of MI. No association was found between MI risk and cumulative exposure to nevirapine, efavirenz, nelfinavir, or saquinavir. Cumulative exposure to indinavir and lopinavir-ritonavir was associated with an increased risk of MI (relative rate [RR] per year, 1.12 and 1.13, respectively). These increased risks were attenuated slightly (RR per year, 1.08 [95% confidence interval {CI}, 1.02-1.14] and 1.09 [95% CI, 1.01-1.17], respectively) after adjustment for lipids but were not altered further after adjustment for other metabolic parameters. CONCLUSIONS. Of the drugs considered, only indinavir, lopinavir-ritonavir, didanosine, and abacavir were associated with a significantly increased risk of MI. As with any observational study, our findings must be interpreted with caution (given the potential for confounding) and in the context of the benefits that these drugs provide.

Background. This study was performed to investigate the concordance between commonly used human immunodeficiency virus type 1 (HIV-1) drug resistance interpretation systems for didanosine (ddI) and their ability to predict responses at weeks 8 and 24. Methods. The study included drug-experienced HIV-infected patients who had viral loads >500 copies/mL and who underwent a genotypic resistance test when beginning a ddI-containing therapy. The interpretations of the level of resistance to ddI were compared for the 6 interpretation systems. Linear and logistic regression were used to assess their ability to predict responses for weeks 8 and 24, respectively. Results. The 1453 patients had a median viral load of 4.3 logic copies/mL, and 31% were preexposed to ddl. Complete concordance was found for 19% of samples, partial discordance for 49%, and complete discordance for 32%. The median viral load reduction at week 8 was 1.36 logic 10 copies/mL, and 56% of patients had viral loads >400 copies/mL at week 24. At week 8, all systems correctly predicted a greater viral load reduction in patients with susceptible viruses than in those with resistant viruses, but only the Stanford system was able to discriminate between patients with resistant, intermediately resistant, and susceptible viruses. No systems predicted virological response correctly at week 24. Conclusions. Our results show the need for standardized methods to establish genotypic interpretation systems.

OBJECTIVES To estimate the risk of death and examine the predictors of death and virological/immunological response, following diagnosis of multidrug-resistant (MDR) HIV-1 in a UK multicentre cohort of HIV-infected individuals. METHODS Five hundred and seventy-two patients were identified with MDR HIV-1 between 1997 and 2004. Factors associated with survival and virological/immunological response 24-48 weeks after MDR diagnosis were determined by the Poisson and linear regression, respectively. RESULTS Patient characteristics: 86% males; median age 39 years; median CD4 and viral load (VL) at MDR diagnosis 230 cells/mm3 and 4.2 log10 copies/mL; median number of antiretroviral drugs previously exposed to 8. Sixty patients died over a median follow-up of 31 months (IQR: 17-50), giving an estimated mortality rate of 3.7 deaths per 100 person-years (95% CI 2.9-4.7) following MDR diagnosis. In adjusted analysis, higher CD4 count, lower VL, more recent calendar year, lower number of antiretroviral drugs previously exposed to and greater age at MDR diagnosis were associated with an increased chance of survival. There was some evidence of a better virological response at 24-48 weeks after MDR diagnosis in patients who changed regimen compared with patients who did not change regimen. CONCLUSIONS The risk of death following MDR diagnosis may be at least 3-fold the risk observed overall in HIV-infected individuals. Changing antiretroviral therapy following emergence of MDR HIV-1 may be associated with improved short-term virological response.

Objectives To determine prevalence and predictors of antiretroviral drug resistance in newly diagnosed individuals with HIV-1 infection, using a systematic approach to avoid selection bias. Methods Plasma samples from all persons diagnosed HIV-1 seropositive at a large London centre between April 2004 and February 2006 underwent sequencing of HIV-1 reverse transcriptase (RT) and protease genes. Subtype was assigned by phylogenetic analysis. Resistance was scored according to the IAS-USA list (2005) modified to include T215revertants and exclude isolated E44D or V118I and minor protease mutations. Recent seroconversion was identified by HIV antibody avidity testing. Results The cohort of 239 included 169 (70.7%) males, 126 (52.7%) homosexuals, 118 (49.5%) persons of white ethnicity and 144 (60.0%) persons born outside the UK. Subtypes included B 134 (56.1%), C 46 (19.2%), A 17 (7.1%), other non-B 42 (17.6%). The prevalence of resistance mutations was 17/239 (7.1%; 95% confidence interval 4.5-11.1%), comprising 10/239 (4.2%) nucleoside/nucleotide RT inhibitor (NRTI); 4/239 (1.7%) non-nucleoside RT inhibitor (NNRTI) and 4/239 (1.7%) protease inhibitor (PI) associated mutations. Dual-class (NRTI + PI) resistance mutations were detected in 1/239 (0.4%) person. The prevalence of resistance mutations was 7/85 (8.2%) and 10/154 (6.5%) in persons with recent and established infection, respectively. In multivariate analysis, having been born in the UK and high CD4 count, but not gender, age, risk group, ethnicity or subtype, were independent predictors of resistance. Conclusions In an unselected UK cohort, subtypes other than B accounted for 43.9% of new HIV-1 diagnoses. The prevalence of resistance mutations was 7.1% and highest in those born in the UK.

Background. Limited data exist on factors predicting the development of opportunistic infections (OIs) at higher-than-expected CD4(+) cell counts in human immunodeficiency virus (HIV) type 1-infected adults. Methods. Multivariate Poisson regression models were used to determine factors related to the development of groups of OIs above their respective traditional upper CD4(+) cell count thresholds: group 1 (>= 100 cells/mu L), OIs caused by cytomegalovirus, Mycobacterium avium complex, and Toxoplasma gondii; group 2 (>= 200 cells/mu L), Pneumocystis pneumonia and esophageal candidiasis; and group 3 (>= 300 cells/mu L), pulmonary and extrapulmonary tuberculosis. Results. In groups 1, 2, and 3, 71 of 9219, 125 of 7934, and 36 of 7838 patients, respectively, developed >= 1 intragroup OI. The strongest predictor of an OI in groups 1 and 2 was current CD4(+) cell count (for group 1, incidence rate ratio [IRR] per 50% lower CD4(+) cell count, 5.37 [95% confidence interval {CI}, 3.71-7.77]; for group 2, 4.28 [95% CI, 2.98-6.14]). Injection drug use but not current CD4(+) cell count predicted risk in group 3. Use of antiretroviral treatment was associated with a lower incidence of OIs in all groups, likely by reducing HIV-1 RNA levels (IRR per 1-log(10) copies/mL higher HIV-1 RNA levels for group 1, 1.50 [95% CI, 1.15-1.95]; for group 2, 1.68 [95% CI, 1.40-2.02]; and for group 3, 1.89 [95% CI, 1.40-2.54]). Conclusion. Although the absolute incidence is low, the current CD4(+) cell count and HIV-1 RNA level are strong predictors of most OIs in patients with high CD4(+) cell counts.

Relatively few data are available on the association between the use of specific antiretroviral drugs and the rate of viral rebound in those attaining a viral load (VL)50 copies/mL while receiving highly active antiretroviral therapy (HAART).Patients achieving a VL50 copies/mL for the first time while receiving HAART were followed until viral rebound (2 consecutive VLs500 copies/mL). Pre-HAART antiretroviral-naive patients were analyzed separately from those with nucleoside reverse transcriptase inhibitor (NRTI) experience.Of 3565 suppressed antiretroviral-naive patients, 381 experienced viral rebound (rate, 6.26 events/100 person-years of follow-up [pyrs] [95% confidence interval {CI}, 5.63-6.89 events/100 pyrs]). For those receiving efavirenz, the rate was 4.08 (95% CI, 3.16-5.01) events/pyrs. Compared with this, the rebound rate for those receiving indinavir was 1.52 times higher (rate ratio [RR], 1.52 [95% CI, 0.82-2.84]). RRs (95% CIs) for other drugs were: soft-gel saquinavir, 0.54 (0.07-3.97); nelfinavir, 2.44 (1.68-3.54); indinavir/ritonavir, 1.96 (1.02-3.77); saquinavir/ritonavir, 1.12 (0.48-2.61); lopinavir/ritonavir, 1.23 (0.58-2.59); nevirapine, 1.53 (1.11-2.10); and abacavir, 2.03 (1.26-3.25). Of 810 NRTI-exposed patients, 145 experienced viral rebound (rate, 8.29 [95% CI, 6.94-9.64] events/pyrs). For those receiving efavirenz, the rate was 5.25 (95% CI, 3.11-8.30) events/pyrs. Compared with this, the RRs (95% CIs) were: indinavir, 1.75 (0.82-3.73); hard-gel saquinavir, 3.48 (0.36-33.37); nelfinavir, 2.64 (1.37-5.08); indinavir/ritonavir, 0.32 (0.04-2.49); saquinavir/ritonavir, 0.64 (0.23-1.80); nevirapine, 1.65 (0.90-3.02); and abacavir, 1.82 (0.73-4.52).We must make comparisons of antiretroviral outcomes in observational data with caution; however, our results suggest that, in those with VLs50 copies/mL, certain drugs may be associated with higher rebound rates than others.

Buzan and Lawson (2012) ( International Studies Quarterly ) persuasively argue that IR scholars must pay greater attention to the nineteenth-century global transformation. Nevertheless, their account would be strengthened by a greater acknowledgment of the critical role indigenous intermediaries played in facilitating Western colonialism, and also by a clearer recognition of the limited and late impact that rational state-building and ideologies of progress exerted on the shape of Western colonial empires. These amendments are necessary to avoid overstating the distinctiveness of modern empires relative to their pre-nineteenth-century forerunners, and thereby missing the true significance of the twentieth-century “big bang” that saw empires’ ruin and replacement by a global sovereign state monoculture.

This study evaluated 1433 human immunodeficiency virus (HIV)–infected patients starting highly active antiretroviral therapy (HAART), 409 (28%) of whom had prior nucleoside experience and achieved an HIV load of !400 copies/mL by 24 weeks of therapy. Three hundred seven patients experienced virus rebound during a total of 2773.3 person-years of follow-up. There was a higher rate of virus rebound among the patients with pre-HAART nucleoside experience (relative hazard [RH], 2.86; 95% confidence interval, 2.22–3.84; ) and a P ! .0001 decreasing rate of virus rebound with increasing duration of virus suppression (i.e., time since achieving a virus load of !400 HIV RNA copies/mL) among both the nucleoside-experienced and naive patients ( ), but the difference between the groups persisted into the third P ! .0001 year of follow-up ( ). Even patients who had experienced !2 months of nucleoside P p .0007 therapy before beginning HAART had an increased risk of virus rebound (RH, 1.95; P p ). It appears that only a small period of pre-HAART nucleoside therapy is sufficient to .009 confer a disadvantage, in terms of risk of virus rebound, that persists for several years.

BACKGROUND: Although studies have reported large reductions in the risks of AIDS and death since the introduction of potent anti-retroviral therapies, few have evaluated whether this has been similar for all AIDS-defining diseases. We wished to evaluate changes over time in the risk of specific AIDS-defining diseases, as first events, using data from individuals with known dates of HIV seroconversion. METHODS: Using a competing risks proportional hazards model on pooled data from 20 cohorts (CASCADE), we evaluated time from HIV seroconversion to each first AIDS-defining disease (16 groups) and to death without AIDS for four calendar periods, adjusting for exposure category, age, sex, acute infection, and stratifying by cohort. We compared results to those obtained from a cause-specific hazards model. RESULTS: Of 6,941, 2,021 (29%) developed AIDS and 437 (6%) died without AIDS. The risk of AIDS or death remained constant to 1996 then reduced; relative hazard = 0.89 (95% CI: 0.77-1.03); 0.90 (95% CI: 0.81-1.01); and 0.32 (95% CI: 0.28-0.37) for 1979-1990, 1991-1993, and 1997-2001, respectively, compared to 1994-1996. Significant risk reductions in 1997-2001 were observed in all but two AIDS-defining groups and death without AIDS in a competing risks model (with similar results from a cause-specific model). There was significant heterogeneity in the risk reduction across events; from 96% for cryptosporidiosis, to 17% for death without AIDS (P < 0.0001). CONCLUSION: These findings suggest that studies reporting a stable trend for particular AIDS diseases over the period 1979-2001 may not have accounted for the competing risks among other events or lack the power to detect smaller trends.

The association between CD4 cell count and duration of virus load suppression was investigated in 558 patients in the Frankfurt HIV Clinic Cohort who had begun highly active antiretroviral therapy and who had virus load declines to/=500 copies/mL. The Kaplan-Meier method estimated viral rebound in 42.5% of patients by 24 weeks and in 64.3% by 84 weeks. Risk of viral rebound was independently associated with baseline and changes from baseline CD4 cell count. The achieved CD4 cell count was the most important factor for prediction of viral rebound (relative hazard, 5.4 for an updated CD4 cell count of20 vs.500 copies/mL; P=.0001). Baseline virus load was not associated with virus load rebound. Lower baseline CD4 cell counts were associated with increased risk of viral rebound; however, this risk was significantly reduced in persons with low baseline CD4 cell counts who experienced substantial increases in CD4 cell counts during follow-up.

Human immunodeficiency virus type 1 (HIV-1) strains dually resistant to zidovudine and lamivudine (3TC) may arise during zidovudine-3TC combination therapy. The objective of this cross-sectional study (n = 43 patients) was to test the association between therapy response (clinical and immunologic) to zidovudine-3TC and the level of phenotypic zidovudine resistance and zidovudine resistance-associated genotype of 3TC-resistant isolates. Other variables included were baseline CD4 + cell count, baseline Centers for Disease Control and Prevention (CDC) classification, virus load, and time receiving zidovudine. Phenotypic resistance was assessed using a recombinant virus assay. Genotypic analysis was based on population sequencing of plasma HIV-1. In a univariate analysis using a logistic regression model, it was found that therapy response was significantly associated with phenotypic and genotypic zidovudine resistance, baseline CD4 + cell count, and virus load. After adjustment for all variables, phenotypic resistance to zidovudine remained the only significantly associated factor, independent of baseline CD4 + cell count, baseline CDC classification, and virus load.

Because considerable information about progression of human immunodeficiency virus (HIV) infection has been provided by studies of cohorts of individuals with prevalent HIV infection, this study was designed to investigate bias due to onset confounding (differential time-since-infection distributions) and differential length-biased sampling in epidemiologic analyses of data from such cohorts. Subjects were participants in the Italian Seroconverters Study, a seroincident cohort of more than 1,200 adults seen at ambulatory care clinics in Italy, with observed HIV seroconversion in 1980-1988. Acquired immunodeficiency syndrome (AIDS) diagnoses, based on the 1987 Centers for Disease Control case definition, and mortality were ascertained through Italian national registries through 1994. To estimate bias in prevalent cohorts, a series of pseudo-seroprevalent (PSP) cohorts were drawn by sampling, from among the total seroincident cohort, prevalent AIDS-free subjects in each calendar year. The relative AIDS risk associated with a given covariate was calculated in each PSP cohort and compared with the relative AIDS risk for that covariate in the seroincident cohort. Relative risks were estimated by both the ratio of AIDS incidence densities and the relative AIDS hazards from proportional hazards regression. Differential length bias was not evident, as assessed in the following way: Among 338 individuals with seroconversion dates in 1983-1986, the relative risk of AIDS for subjects born before 1951 compared with those born more recently was 1.67 (95% confidence interval (CI) 1.30-2.14). Although differential length-biased sampling was expected to bias this relative risk toward 1.0, the observed relative risk for earlier birth ranged from 1.79 to 2.86 in 1987-1992 PSP cohorts, Onset bias was observed: Among 644 subjects with seroconversion in 1980-1988, the AIDS relative risk for 1980-1985 seroconverters compared with 1986-1988 seroconverters was 1.09 (95% CI 0.76-1.55). Onset bias was seen in 1988-1990 PSP cohorts (relative risks for early seroconversion = 1.47, 1.46, and 1.34, respectively); in 1991-1992, relative risks were close to the expected value of 1.09, and Cls on relative risks from all PSP cohorts after 1989 included 1.0. Confounding attributable to differential length-biased sampling in prevalent cohorts does not necessarily bias estimates of the impact of covariates on rate of progression to AIDS. Bias can arise when a covariate suspected of affecting AIDS risk is closely linked to date of acquisition of HIV infection. However, onset bias appears to wane as subjects' dates of infection become more remote.

It has been suggested that the rate of CD4 cell decline accelerates in parallel with decreasing numbers of cells; however, the statistical literature suggests the opposite, CD4 cells were counted about every 6 months in a cohort of 1264 human immunodeficiency virus-infected subjects (the Italian Seroconversion Study cohort), Kaplan-Meier analysis was used to estimate the time for CD4 cells to decline by 100 cells/mm(3), conditional on reaching predefined levels, In addition, CD4 cell counts were modeled as a function of time since seroconversion in individuals with greater than or equal to 5 counts, Kaplan-Meier survival times for a 100 cell/mm(3) decrease in CD4 cells increased as lower counts were reached (log rank test, P

To assess the influence of hepatitis C virus (HCV) on the natural history of human immunodeficiency virus (HIV) infection, a longitudinal study was conducted among 416 HIV-positive, AIDS-free persons infected through injecting drug use or homosexual or heterosexual activity and with known seroconversion dates. End points were diagnosis of AIDS and a CD4 cell count of < 100 x 10(6) cells/L. HCV antibodies were detected in 214 persons (51.4%). The crude relative hazard (RH) of progression to AIDS was 0.96 (95% confidence interval [CI], 0.53-1.76) for HCV-coinfected participants compared with those not coinfected. After adjustment for CD4 cell count, the RH was 0.97 (95% CI, 0.52-1.79). Similar RHs were found using a CD4 cell count of < 100 x 10(6) cells/L as the end point. The median CD4 cell loss was 4.83 x 10(6) cells/L per month among coinfected persons and 5.70 x 10(6) cells/L per month among the others. These results suggest that coinfection with HCV does not influence clinical and immunologic progression of HIV disease.

International audience; Many questions about the long-term effects of combination antiretroviral therapy (cART) on clinical outcomes in people living with HIV (PLWH) and their impact on health systems remain unanswered. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) was formed in 2005 to pool and harmonize existing longitudinal data on people living with HIV in Europe, to answer key research questions that could not be addressed adequately by individual cohorts. Key research questions include long-term prognosis, rare outcomes, and variations across patient groups, settings and health systems. COHERE uses the HIV Cohorts Data Exchange Protocol, a standardized and validated method of data structure and transfer, to compile data from over 40 cohorts of PLWH residing in Europe, representing 331 481 individuals, including 2808 children (

The loss of CD4 lymphocytes is known to be an important component of human immunodeficiency virus type 1 (HIV-1) pathogenesis. It remains unclear, however, whether the importance of the CD4 lymphocyte count is such that individuals who have been infected for widely different lengths of time, but for whom the CD4 lymphocyte count is the same, have the same risk of developing acquired immunodeficiency syndrome (AIDS). The authors directly addressed this question for 111 HIV-1-infected hemophiliacs who had been followed for up to 12 years from seroconversion and for whom a median of 16 CD4 lymphocyte counts had been made. Thirty-eight patients had developed AIDS by January 1, 1992. As of August 1, 1985, the time from sero-conversion to AIDS ranged from 3 weeks to almost 6 years. The risk of AIDS increased with time from seroconversion (relative hazard = 1.25 per year; p = 0.09). CD4 lymphocyte count was strongly related to time from seroconversion and also to the risk of AIDS (relative hazard = 3.25 per 100/mm(3); p < 0.00005). In a bivariate Cox regression model, the relative hazard for time from seroconversion fell markedly towards unity (1.05; p = 0.7), while that for CD4 lymphocyte count remained unchanged. This suggests that time from seroconversion is a relevant factor in HIV-1 infection only insofar as it provides information as to the probable degree of loss of CD4 lymphocytes. If the number of these cells is known, time from seroconversion seems to be of little additional value in assessing the risk of AIDS. This finding has implications for the clinical assessment of individual patient prognosis, for the design of epidemiologic studies of HIV-1 infection, and for our understanding of how HIV-1 causes disease.

To the Editor—Highly active antiretroviral therapy (HAART) appears to significantly reduce the risk of clinicalAIDSand death over the course of at least 3–5 years of follow-up in patients with high CD4 cell counts (e.g., 1350 cells/mm 3 ), although the absolute reduction in risk is not as great as it is in patients with lower CD4 cell counts [1, 2]. The data in the interesting paper by Wang et al. [3] on mortality in injection drug users (IDUs) are consistent with this. Indeed, Wang et al. showed that mortality in HIV-seropositive patients who began HAART when they had CD4 cell counts 1350 cells/mm 3 may be as low as that in HIVseronegative IDUs. We would conclude that, if one is concerned only with this time span (and these outcomes), thenthe immediate initiation of HAART is preferable to deferring therapy, even in patients with high CD4 cell counts. However, most patients justifiabl have a much longer-term perspective than that. Because some of the key benefit of deferring HAART can, by definition only be realized during the longer term, follow-up times of at least 10 years areprobably needed before it is possible to ascertain whether these benefit start to outweigh the clear early disadvantages of deferral. This is, of course, if we can also address the other issues that we all face in performing such analyses—recruiting sufficien numbers of patients and having no important residual biases (due to confounding, informative censoring caused by loss to follow-up, or other sources). We therefore feel that Wang et al.’s conclusion, which suggests that HAART should be in