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Objective To examine the independent association between intimate partner violence (IPV) severity and all-cause mortality among women living with HIV (WLHIV). Design Cross-sectional questionnaire linked to longitudinal vital statistics data. Methods We examined the lifetime prevalence of IPV and age-standardized all-cause mortality rates by IPV severity reported by WLHIV. Lifetime IPV (emotional/verbal, physical, or sexual) severity was assessed as a categorical variable: no history of any IPV (none); experienced one or two forms of IPV (moderate); or experienced all three forms of IPV (severe IPV). Two separate logistic regression models examined associations between any IPV (vs. none) as well as IPV severity (none vs. moderate, severe) and all-cause mortality. Results At the time of interview (2007-2010), 260 participants self-identified as women with a median (Q1-Q3) age of 41 years (35-46). Of these women, the majority were unemployed (85%), 59% reported any IPV and 24% reported severe IPV. Of the 252 women followed until 31 December 2017, 25% (n = 63) died. Age-standardized all-cause mortality rates for WLHIV who experienced severe IPV were two-times higher than women with no history of IPV (44.7 per 1000 woman-years vs. 20.9 per 1000 woman-years). After adjustment for confounding, experiences of severe IPV (vs. none) were significantly associated with all-cause mortality (aOR = 2.42, 95% CI = 1.03-5.70). Conclusion Although we found that any lifetime experience of IPV was not associated with all-cause mortality, women ever experiencing severe IPV were significantly more likely to die during the study period. This may suggest a need for increased trauma- and violence-aware approaches.

OBJECTIVES: Although previous cross-sectional studies have identified correlates of detectable plasma HIV-1 RNA viral load (VL) among HIV-positive people who use drugs (PWUD), longitudinal factors associated with heightened HIV transmission potential have not been well described. Therefore, we longitudinally examined factors associated with amount of person-time spent above log(10)(1500) copies/ml plasma among HIV-positive PWUD in Vancouver, Canada. DESIGN: Data were derived from a long-running prospective cohort of HIV-positive PWUD linked to comprehensive clinical records including systematic VL monitoring. METHODS: We used generalized estimating equations modeling to longitudinally examine factors associated with person-time (in days) with a VL more than log(10)(1500) copies/ml plasma in the previous 180 days. RESULTS: Between December 2005 and May 2014, 845 PWUD were eligible and included in the study. Participants spent an average of 26.8% of observation time with a VL more than log(10)(1500) copies/ml. In multivariable analyses, homelessness (Adjusted Rate Ratio [ARR] = 1.45) and lack of social support (ARR = 1.27) were positively associated with person-time with a VL more than log(10)(1500) copies/ml. Older age (ARR = 0.97) and enrolment in addiction treatment (ARR = 0.75) were negatively associated with the outcome in multivariable analyses (all P < 0.05). CONCLUSION: Social and structural factors, including periods of homelessness or lacking in social support, were independently associated with greater amount of time with heightened HIV transmission potential. These findings suggest the need for targeted efforts to address modifiable contextual factors that contribute to increased risk of onward HIV transmission among PWUD.

Objectives To describe and compare integrase strand transfer inhibitor (INSTI) adverse drug reactions (ADRs) for raltegravir, elvitegravir-cobicistat, and dolutegravir. Design Population-based, retrospective cohort. Methods Antiretroviral-experienced and naive persons at least 19 years old were included if they received their first prescription for raltegravir, elvitegravir-cobicistat, or dolutegravir in British Columbia, Canada, in 2012-2014, and were followed for 2 years until 31 December 2016. The primary outcome was an ADR resulting in INSTI discontinuation. ADR rates and 95% confidence intervals (95% CIs) were calculated by Poisson method. Cox proportional-hazards regression estimated the hazard ratio for ADR-related INSTI discontinuation, adjusted for confounders. ADR symptoms were compared across INSTIs. Results There were 1344 persons contributing 1464 person-INSTI exposures. The cohort was predominantly male (79%) and antiretroviral therapy-experienced (85%). ADR events and unadjusted ADR rates (95% CI) per 100 person-years were raltegravir 24 of 551 (4.4%), 2.91 (1.95, 4.35); elvitegravir-cobicistat 38 of 394 (9.6%), 5.94 (4.32, 8.16); and dolutegravir 27 of 519 (5.2%), 2.96 (2.03, 4.31). The ADR rate for elvitegravir-cobicistat was double that of dolutegravir (adjusted hazard ratio 2.24, 95% CI 1.13, 4.44), but not significantly different for either dolutegravir or elvitegravir versus raltegravir. Elvitegravir-cobicistat-treated persons had a significantly higher proportion of gastrointestinal and general (fatigue, malaise) ADRs. Neuropsychiatric ADRs were more frequent with dolutegravir, but not significantly different between INSTIs. Among those switching between INSTIs, there was no apparent relationship between experiencing an ADR to one INSTI and subsequent intolerance to another. Conclusions This study affirms INSTIs are well tolerated during routine clinical use. Consideration of differences in side effect profiles can inform antiretroviral therapy individualization.

Objectives To estimate the incidence of and risk factors for emergent resistance to integrase strand transfer inhibitor (INSTI) and nucleoside(-tide) reverse transcriptase inhibitors (NRTI) in HIV-1-infected adults receiving an INSTI and two NRTIs. Design Retrospective cohort study. Methods Persons aged at least 19 years were included if they received their first prescription for raltegravir, elvitegravir or dolutegravir in British Columbia, Canada in 2012-2014 and were followed to 31 December 2015. Emergent resistance was defined as new mutations conferring intermediate-high level NRTI or INSTI resistance (score ≥30, Stanford HIV Drug Resistance Algorithm v.7.0.1). First-year resistance rates and 95% confidence intervals (95% CI) were estimated for 'any' (INSTI or NRTI) resistance using Poisson regression. The relationship between any emergent resistance and explanatory variables was modeled by Cox proportional hazards. Results There were 270 raltegravir, 323 elvitegravir and 392 dolutegravir-treated persons who were predominantly male (77%), antiretroviral therapy (ART)-experienced (81%), with low prevalence of preexisting drug resistance (16%). INSTI and NRTI resistance emerged in both ART-experienced and ART-naive persons (including dolutegravir-treated ART-naive), with no statistically significant differences in 'any' resistance rates (95% CI) between INSTIs: raltegravir 3.80 (1.90, 7.60), elvitegravir 2.37 (1.06, 5.27) and dolutegravir 1.48 (0.62, 3.55)/100 person-years. The strongest factors associated with emergent resistance were CD4 less than 200 cells/μl, adjusted hazard ratio (95% CI) 10.46 (4.67, 23.41) and less than 80% adherence to the INSTI regimen hazard ratio 2.52 (1.11, 5.71). Conclusion Incident drug resistance rates were low with 'real-world' use of INSTI-based regimens. However, incomplete ART adherence and low CD4 cell count were associated with increased resistance rates regardless of which INSTI was prescribed. Provide adherence support and monitor for drug resistance.

To characterize the safety profile of tenofovir disoproxil fumarate (DF) for the treatment of HIV infection in adults over the first 4 years of use. A tenofovir DF expanded access program (EAP) was initiated in 2001; safety data were examined from this program and from the manufacturer's database, which contained reports of all postmarketing adverse drug reactions received up to 30 April 2005. Specific analyses were performed to characterize the renal safety of tenofovir DF. The EAP enrolled 10 343 patients; serious adverse events (SAEs) were reported in 631 (6%). A renal SAE of any type was observed in 0.5% of patients, and graded elevations in serum creatinine occurred in 2.2% of the patients evaluated. In a multivariate analysis, baseline risk factors for the development of increased serum creatinine on-study were elevated serum creatinine, concomitant nephrotoxic medications, low body weight, advanced age, and lower CD4 cell count. For postmarketing safety data (455 392 person-years of exposure to tenofovir DF) the most commonly reported serious adverse drug reactions were renal events, with a distribution by type similar to that observed in the EAP. Bone abnormalities were infrequently reported in either the EAP or the postmarketing safety databases. No new unexpected toxicities were identified in postmarketing safety surveillance. The data demonstrate a favorable safety profile for tenofovir DF in the treatment of adults with HIV infection. Risk factors for development of nephrotoxicity can be identified and may be useful in managing those patients at greatest risk

OBJECTIVE We sought to estimate the change in viral suppression prevalence if homelessness were eliminated from a population of HIV-infected people who use drugs. DESIGN Community-recruited prospective cohort of HIV-infected people who use drugs in Vancouver, Canada. Behavioural information was collected at baseline and linked to a province-wide HIV/AIDS treatment database. The primary outcome was viral suppression (

Objective Given that people who use illicit drugs (PWUD) often engage in prohibited income generation to support their basic needs, we sought to examine the role of these activities in shaping antiretroviral therapy (ART) adherence and plasma HIV RNA-1 viral load suppression among HIV-infected PWUD. Design Longitudinal analyses among HIV-positive, ART-exposed PWUD in the AIDS Care Cohort to evaluate Exposure to Survival Services prospective cohort study (2005-2013). Methods Generalized linear mixed-effects and mediation analyses examined the relationship between prohibited income generation (e.g., sex work, drug dealing, theft, street-based income) and virologic suppression (plasma viral load ≤50 copies/ml plasma) adjusting for adherence and potential confounders. Results Among 687 HIV-infected PWUD, 391 (56.9%) individuals reported prohibited income generation activity during the study period. In multivariate analyses, prohibited income generation remained independently and negatively associated with virologic suppression (adjusted odds ratio: 0.68, 95% confidence interval: 0.52-0.88) following adjustment for hypothesized confounders, including high-intensity drug use, ART adherence and homelessness. Although partially mediated by ART adherence, the relationship between prohibited income generation and virologic suppression was maintained in mediation analyses (Sobel statistic = -1.95, P = 0.05). Conclusion Involvement in prohibited income generation decreases the likelihood of virologic suppression directly and indirectly through its negative association with ART adherence. These findings suggest that linkages between socioeconomic marginalization, the criminalization of illicit drug use, and insufficient employment opportunities may produce barriers to access and retention in care. Programmatic and policy interventions that decrease socioeconomic vulnerability may therefore reduce HIV-related morbidity, mortality, and onward transmission.

People who inject drugs (PWID) account for roughly 13% of the prevalent HIV/AIDS population outside of sub-Saharan Africa, and access to opioid substitution treatment (OST) is limited in many settings globally. OST likely facilitates access to HAART, yet sparse evidence is available to support this hypothesis. Our objective was to determine the causal impact of OST exposure on HAART adherence among HIV-positive PWID in a Canadian setting.We executed a retrospective cohort study using linked population-level data for British Columbia, Canada (January 1996-March 2010). We considered HIV-positive PWID after meeting HAART initiation criteria. A marginal structural model was estimated on a monthly timescale using inverse probability of treatment weights. The primary outcome was 95% HAART adherence, according to pharmacy refill compliance. Exposure to OST was defined as 95% of OST receipt, and we controlled for a range of fixed and time-varying covariates.Our study included 1852 (63.3%) HIV-positive PWID with a median follow-up of 5.5 years; 34% were female and 39% had previously accessed OST. The baseline covariate-adjusted odds of HAART adherence following OST exposure was 1.96 (95% confidence interval: 1.72-2.24), although the adjusted odds estimated within the marginal structural model was 1.68 (1.48-1.92). Findings were robust to sensitivity analyses on model specification.In a setting characterized by universal healthcare and widespread access to both office-based OST and HAART, OST substantially increased the odds of HAART adherence. This underlines the need to address barriers to OST globally to reduce the disease burden of both opioid dependence and HIV/AIDS.

OBJECTIVE Antiretrovirals do not prevent anal intraepithelial neoplasia. However, the influence of antiretrovirals in the natural history of invasive anal cancer is less clear. The objective is to investigate the impact of antiretrovirals in the time to the development of anal cancer in HIV-positive MSM. DESIGN A retrospective analysis of cases of anal cancer in a cohort of HIV-positive MSM receiving antiretrovirals between 1988 and 2008. METHODS Time from first CD4 cell count or HIV RNA viral load test to anal cancer diagnosis was analysed using Cox regression and Kaplan-Meier curves. Anal cancer cases treated in the era prior to HAART (

Objective(s): We investigated the probability of transitioning in or out of the CD3+ T-cell homeostatic range during antiretroviral therapy, and we assessed the clinical impact of lost T-cell homeostasis (TCH) on AIDS-defining illnesses (ADIs) or death. Design: Within the Canadian Observational Cohort (CANOC), we studied 4463 antiretroviral therapy (ART)-naive HIV-positive patients initiating combination ART (cART) between 2000 and 2010. Methods: CD3+ trajectories were estimated using a four state Markov model. CD3+ T-cel percentage states were classified as follows: very low ( 85%). Covariates associated with transitioning between states were examined. The association between CD3+ T-cell percentage states and time to ADI/death from cART initiation was determined using Cox proportional hazards models. Results: A total of 4463 patients were followed for a median of 3 years. Two thousand, five hundred and eight (56%) patients never transitioned from their baseline CD3+ T-cell percentage state; 85% of these had normal TCH. In multivariable analysis, individuals with time-updated low CD4+ cell count, time-updated detectable viral load, older age, and hepatitis C virus (HCV) coinfection were less likely to maintain TCH. In the multivariable proportional hazards model, both very low and high CD3+ T-cell percentages were associated with increased risk of ADI/death [adjusted hazard ratio=1.91 (95% confidence interval, CI: 1.27–2.89) and hazard ratio=1.49 (95% CI: 1.13–1.96), respectively]. Conclusion: Patients with very low or high CD3+ T-cell percentages are at risk for ADIs/death. To our knowledge, this is the first study linking altered TCH and morbidity/mortality in cART-treated HIV-positive patients.

BACKGROUND: Current guidelines state that the goal of antiretroviral therapy for HIV-infected individuals is to suppress plasma viral load (pVL) to below 400 copies/ml. METHODS: Predictors of achieving and maintaining pVL suppression were examined in a randomized trial of combinations of zidovudine, nevirapine and didanosine in patients with CD4+ T cell counts of between 200 and 600 x 10(6) cells/l who were naive to antiretroviral therapy and AIDS-free at enrolment. RESULTS: One hundred and four patients had pVL > 500 copies/ml at baseline and a pVL nadir below 500 copies/ml. Of these, 77 patients experienced an increase in pVL above 500 copies/ml. The median number of days of pVL suppression to below 500 copies/ml was 285 (42) for patients with pVL nadir ) 20 copies/ml (P = 00.0001). The relative risk of an increase in pVL above 500 copies/ml associated with a pVL nadir below 20 copies/ml was 0.11 (P = 0.0001). The relative risks of an increase in pVL above 5000 copies/ml associated with a pVL nadir below 20 copies/ml or between 20 and 400 copies/ml were 0.05 [95% confidence interval (CI), 0.02-0.12] and 0.37 (95% CI, 0.23-0.61) respectively, compared with individuals with a pVL nadir > 400 copies/ml. Individuals with a pVL nadir

OBJECTIVE Studies focusing on HIV-hepatitis C virus (HCV) coinfected individuals without a history of IDU are limited. It is plausible that poorer clinical outcomes in HIV-HCV coinfection are due to factors associated with IDU, not from HCV itself. This study compares HIV treatment outcomes and survival between HIV-HCV coinfected individuals with and without IDU history. DESIGN Observational cohort study. METHODS We analyzed data from a multisite Canadian cohort study of HIV-positive individuals initiating combination antiretroviral therapy (ART) after 1 January 2000. This analysis was restricted to 1254 participants with HCV coinfection and known IDU history. Cox proportional hazards regression was used to evaluate time from ART initiation to virologic suppression (two consecutive measures

Objective Although antiretroviral therapy (ART) dramatically reduces viral load and improves survival among HIV-infected injection drug users (IDUs), several short-term studies have raised concerns that ART initiation may result in increases in sexual risk behaviour among IDUs. Design We used data from a long-running cohort of HIV-positive IDUs to examine whether ART initiation was associated with increases in several measures of sexual risk behaviour. The date of ART initiation was determined through a validated linkage to a centralized ART dispensation pharmacy. Methods We used generalized linear mixed-effects modelling to examine whether sexual activity, unprotected intercourse, and multiple sexual partnerships were more likely in the 12-month period following ART initiation. Results Among 457 individuals who were ART naive at baseline, the median age was 34 [interquartile range (IQR) 28-41] and 202 (44.2%) were women. Between May 1996 and April 2008, 260 (56.7%) participants initiated ART. In multivariate analyses, ART initiation was not associated with sexual activity [adjusted odds ratio (AOR) = 0.87, 95% confidence interval (CI) 0.60-1.25], unprotected intercourse (AOR = 0.82, 95% CI 0.51-1.31), or multiple sexual partnerships (AOR = 0.93, 95% CI 0.61-1.40). Conclusion In this study of HIV-positive IDUs, we failed to detect an increase in sexual risk behaviour during the period following ART initiation. In light of this evidence, and given the known positive effect of ART on survival and its potential role in reducing HIV transmission, concerns regarding potential increases in sexual risk-taking should not undermine the delivery of ART to IDUs.

Globally, injection drug use continues to account for a substantial proportion of HIV infections. There have not, however, been any evidence-based reviews of the barriers and facilitators of HIV treatment among injection drug users. For this review, published studies were extracted from nine academic databases, with no language or date specified in the search criteria. Existing evidence demonstrates that, although injection drug users often have worse outcomes from HIV treatment than non-injection drug users, major antiretroviral-associated survival gains still have been observed among this population. Inferior outcomes are explained by a range of barriers to antiretroviral access and adherence, which often stem from the negative influences of illicit drug policies, as well as issues within medical systems, including lack of physician education about substance abuse. Evidence demonstrates that several under-utilized interventions and novel antiretroviral delivery modalities have helped to greatly address these barriers in several settings, and there is sufficient evidence to support immediate scale-up of these programmes. These interventions include coupling antiretroviral therapy with opioid substitution therapies as well as directly administered antiretroviral therapy programmes. Of particular interest for future evaluation is the coupling of HIV treatment programmes within comprehensive services, which also provide low-threshold (harm reduction) HIV prevention programmes. Scale-up of evidence-based HIV treatment and prevention to injection drug users, however, will require increasing political will among both national policy-makers and international public health agencies.

Liver mitochondrial toxicity is a concern, particularly in HIV/hepatitis C virus (HCV) coinfection. Liver biopsies from HIV/HCV co-infected patients, 14 ON-highly active antiretroviral therapy (HAART) and nine OFF-HAART, were assessed by electron microscopy quantitative morphometric analyses. Hepatocytes tended to be larger ON-HAART than OFF-HAART (P = 0.05), but mitochondrial volume, cristae density, lipid volume, mitochondrial DNA and RNA levels were similar. We found no evidence of increased mitochondrial toxicity in individuals currently on HAART, suggesting that concomitant HAART should not delay HCV therapy.

Enfuvirtide has been a cornerstone of salvage therapy for multidrug-resistant HIV. Raltegravir provides another novel class option, with the advantages of easier administration and improved tolerability. Thirty-five adults electively replaced enfuvirtide with raltegravir while the rest of their regimen was unchanged. All maintained virologic suppression after a median of 7 months except one who experienced a transiently detectable viral load after 5 months. The new regimen was well tolerated with no apparent new drug-related adverse clinical or laboratory events.

Objective: To determine the impact of depressive symptoms on mortality among HIV/ AIDS patients first initiating HAART and the potential role of patient adherence as a confounder and effect modifier in this association. Methods: The study comprised HIV-positive individuals who were first prescribed HAART between August 1996 and June 2002. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Cox proportional hazards models were used to determine the association between depressive symptoms, adherence and all-cause mortality while controlling for several baseline confounding factors. Results: A total of 563 participants met the study inclusion criteria. Of these subjects, 51% had depressive symptoms at baseline and 23% of participants were less than 95% adherent in the first year of follow-up. The overall all-cause mortality rate was 10%. Multivariate analysis showed that individuals with depressive symptoms and adherence < 95% were 5.90 times (95% confidence interval, 2.55-13.68) more likely to die than adherent patients with no depressive symptoms. The estimated median model-based survival probabilities stratified by adherence and depressive symptoms levels ranged from 81 % (interquartile range, 72-89%) for depressive symptoms and adherence < 95% to 97% (interquartile range, 94-98%) for no depressive symptoms and adherence ≥ 95%. Conclusion: The results indicate that both depressive symptoms and adherence were associated with shorter survival among individuals with HIV accessing HAART. Given the high prevalence of depressive symptoms in HIV-positive patients and a strong association with adherence, the findings support improvement in the diagnosis and treatment of depression as well as adherence in order to maximize the effectiveness of HAART.

OBJECTIVE Paired liver biopsies from patients enrolled in the multinational AIDS PEGASYS Ribavirin International Co-infection Trial were analysed to investigate a possible correlation between virological and histological responses. DESIGN AND METHODS A total of 860 HIV-hepatitis C virus (HCV)-co-infected patients were randomly assigned to receive pegIFNalpha-2a (40KD) 180 microg/week plus 800 mg daily ribavirin, pegIFNalpha-2a (40KD) plus placebo or conventional IFNalpha-2a 3 MIU three times a week plus ribavirin for 48 weeks. Paired biopsies were obtained from 401 patients and scored locally using the Ishak-modified histological activity index (HAI). The second biopsy was obtained, on average, 26 weeks or more after the end of treatment. Histological response was defined as a 2-point or greater reduction in the HAI score. RESULTS The histological response rate was significantly higher in patients receiving pegIFNalpha-2a (40KD) plus ribavirin (57%) than in patients receiving pegIFNalpha-2a (40KD) plus placebo (39%; P < 0.017) or IFNalpha-2a plus ribavirin (41%; P = 0.04). Histological response was correlated with virological response, with the histological response rate ranging from 62 to 74% in patients who achieved a sustained virological response (SVR). Histological response was also seen in 32-43% of patients not achieving an SVR. A higher total HAI score was the only prognostic factor for achieving histological response. CONCLUSION The histological response rate was significantly higher in HIV-HCV-co-infected patients who received pegIFNalpha-2a (40KD) plus ribavirin than in those receiving pegIFNalpha-2a (40KD) plus placebo or IFNalpha-2a plus ribavirin. Histological response was correlated with virological response, although a substantial proportion of patients who did not achieve an SVR experienced histological improvement.

Background: The introduction of HAART has led to consistent improvements in survival among HIV-infected individuals. However, there is evidence that not all populations have benefited equally from HAART and that mortality rates are higher in HIV-infected injection drug users than in non-users. Objective: To model life expectancies for HIV-positive individuals subdivided according to history of injection drug use and treatment with HAART. Design: Population-based study of HIV-positive persons in British Columbia's HIV/ AIDS treatment program. Methods: The primary outcome measures in this study were life expectancy at exact age 20 and potential years of life lost. Results: The highest life expectancy (38.9 years) and lowest potential years of life lost were measured for individuals taking HAART and without a history of injection drug use. The lowest life expectancy (19.1 years) and highest potential years of life lost were measured in HIV-positive injection drug users who were not taking HAART. Conclusions: There are substantial disparities in life expectancy for persons living with HIV in British Columbia. Members of the injection drug community, particularly those who are not taking HAART, experience elevated mortality in comparison with those without a history of drug use.

OBJECTIVE: To characterize the impact of hepatitis C (HCV) serostatus on adherence to antiretroviral treatment (ART) among HIV-infected adults initiating ART. METHODS: The British Columbia HIV/AIDS Drug Treatment Program distributes, at no cost, all ART in this Canadian province. Eligible individuals used triple combination ART as their first HIV therapy and had documented HCV serology. Statistical analyses used parametric and non-parametric methods, including multivariate logistic regression. The primary outcome was > or = 95% adherence, defined as receiving > or = 95% of prescription refills during the first year of antiretroviral therapy. RESULTS: There were 1186 patients eligible for analysis, including 606 (51%) positive for HCV antibody and 580 (49%) who were negative. In adjusted analyses, adherence was independently associated with HCV seropositivity [adjusted odds ratio (AOR), 0.48; 95% confidence interval (CI), 0.23-0.97; P = 0.003], higher plasma albumin levels (AOR, 1.07; 95% CI, 1.01-1.12; P = 0.002) and male gender (AOR, 2.53; 95% CI, 1.04-6.15; P = 0.017), but not with injection drug use (IDU), age or other markers of liver injury. There was no evidence of an interaction between HCV and liver injury in adjusted analyses; comparing different strata of HCV and IDU confirmed that HCV was associated with poor adherence independent of IDU. CONCLUSIONS: HCV-coinfected individuals and those with lower albumin are less likely to be adherent to their ART.

BACKGROUND: The HIV-1 envelope third variable loop (V3 loop) is an important determinant of viral phenotype and co-receptor usage. We wished to determine the impact of specific V3 genotypes associated with viral phenotype and co-receptor usage on response to initial triple antiretroviral therapy. METHODS: Pre-therapy plasma samples from the HOMER cohort of 1191 antiretroviral-naive, HIV-infected adults who initiated triple therapy in British Columbia, Canada between August 1996 and September 1999 were genotyped for V3 loop sequence. V3 sequences were dichotomized by the presence or absence of positively charged residues at codons 11 and/or 25 (an '11/25' genotype). Neural network (NN) and Position Specific Scoring Matrix (PSSM) approaches were used as alternative V3 sequence interpretation methods. The association of V3 genotypes with clinical endpoints was assessed over a median of 43 months of follow up. RESULTS: One-hundred and eighteen (10.9%) of the 1085 isolates successfully genotyped for V3 displayed the 11/25 genotype. In multivariate analyses, this genotype was associated with a more rapid CD4 decline [risk ratio, (RR), 1.38; P = 0.012] and earlier mortality (RR, 1.70; P = 0.027), despite comparable viral load suppression below 500 HIV RNA copies/ml. We observed no influence of the 11/25 genotype on time to viral rebound or the development of drug resistance. PSSM-based sequence categories were similarly predictive of outcomes. NN sequence categories were not associated with any endpoints. CONCLUSION: The 11/25 genotype of the HIV V3 loop is an independent predictor of poor immunological response and more rapid mortality even after starting triple antiretroviral therapy. These results may prove to be useful for the clinical management of HIV-infected individuals.

Objective: To calculate the rate of interventional cardiac procedures (ICP) among HIV-infected individuals ever treated with antiretroviral therapy (ART) and to describe clinical and sociodemographic characteristics associated with ICP. Methods: Since 1992, ART in British Columbia (BC) has been centrally distributed by the BC Centre for Excellence in HIV/AIDS. The BC Cardiac Registry maintains information regarding all cardiac procedures performed in BC. The two databases were linked to determine the number of HIV-positive individuals on ART who underwent ICP. Age-adjusted analyses were conducted using direct standardization, and linear regression to test for trend over time. Logistic regression was used to identify patient and treatment characteristics independently associated with having an interventional cardiac procedure. Results: Of the 5082 individuals who have ever received ART, 63 (< 1%) were captured in the Cardiac Registry. There were 97 events: 70 (72%) since 1999. The age-adjusted event rate per 1000 HIV-positive individuals on ART increased significantly over time (P= 0.015) whereas that for the general BC population did not increase over time (P=0.191). In multivariate analysis, age at baseline per 10 year increase [adjusted odds ratio (AOR) 2.5; 95% confidence interval (CI), 1.8-3.2), and months on ART (AOR 1.3; 95% Cl, 1.1-1.4) remained significant. Conclusions: The rate of ICP among HIV-positive individuals on ART appears to be increasing; in addition, the duration of time on ART is independently associated with ICP after adjustment for patient demographic characteristics.

Objective: Therapeutic guidelines advise that 200-350 × 10 6 cells/l may approximate an irreversible threshold beyond which response to therapy is compromised. We evaluated whether non-immune-based factors such as physician experience and adherence could affect survival among HIV-infected adults starting HAART. Methods: Analysis of 1416 antiretroviral naive patients who initiated triple therapy between 1 August 1996 and 31 July 2000, and were followed until 31 July 2001. Patients whose physicians had previously enrolled six or more patients were defined as having an experienced physician. Patients who received medications for at least 75% of the time during the first year of HAART were defined as adherent. Cumulative mortality rates and adjusted relative hazards were determined for various CD4 cell count strata. Results: Among patients with < 50 ×10 6 cells/l the adjusted relative hazard of mortality was 5.07 [95% confidence interval (Cl), 2.50-10.26] for patients of experienced physicians and was 11.99 (95% Cl, 6.33-22.74) among patients with inexperienced physicians, in comparison to patients with ≥ 200 × 10 6 cells/l treated by experienced physicians. Similarly, among patients with < 50 × 10 6 cells/I, the adjusted relative hazard of mortality was 6.19 (95% Cl, 3.03-12.65) for adherent patients and was 35.71 (95% Cl, 16.17-78.85) for non-adherent patients, in comparison to adherent patients with ≥ 200 × 10 6 cells/I. Conclusion: Survival rates following the initiation of HAART are dramatically improved among patients starting with CD4 counts < 200 × 10 6 cells/l once adjusted for conservative estimates of physician experience and adherence. Our results indicate that the current emphasis of therapeutic guidelines on initiating therapy at CD4 cell counts above 200 × 10 6 cells/I should be re-examined.

Introduction: Co-infection with GBV-C (`Hepatitis G’ virus) appears to be associated with slower disease progression in HIV-infected, untreated individuals. We wished to determine whether detection of GBV-C RNA was associated with differential response to HIV therapy in a population-based cohort of 461 individuals initiating antiretroviral therapy between June 1996 and August 1998, in British Columbia, Canada. Methods: The presence of GBV-C RNA in plasma was identified by nested RT–PCR, using detection of HIV gag RNA as a positive control. Time to virological success [achieving HIV plasma viral load (pVL) ≤ 500 copies/ml], virological failure (subsequent confirmed pVL > 500 copies/ml) and immunological failure (confirmed CD4 cell count below baseline) were assessed by Kaplan–Meier methods and Cox proportional hazard regression. Results: Of the 441 individuals for whom results were available, 90 (20.4%) had detectable plasma GBV-C RNA. GBV-C RNA was significantly associated with a lower HIV pVL at baseline (P = 0.004). In univariate and multivariate Cox models, GBV-C RNA positive and negative individuals did not differ with respect to time to virological success [risk ratio (RR), 0.98; 95% confidence interval (CI), 0.75–1.27], time to virological failure (RR, 1.10; 95% CI, 0.74–1.65), or time to immunological failure (RR, 1.09; 95% CI, 0.73–1.63). There was no correlation between detection of GBV-C RNA and mutations in the human chemokine receptors CCR5 and CX3CR1, or HIV viral tropism as predicted by the HIV envelope sequence (P > 0.1). Conclusion: GBV-C viremia is relatively common in individuals seeking treatment for HIV infection; however, it does not appear to have any effect on initial antiretroviral therapy response.

To describe the characteristics and predictors of transient plasma viral load (pVL) rebounds among patients on stable antiretroviral therapy and to determine the effect of one or more pVL rebounds on virological response at week 52.Individual data were combined from 358 patients from the INCAS, AVANTI-2 and AVANTI-3 studies. Logistic regression models were used to determine the relationship between the magnitude of an increase in pVL and the probability of returning to the lower limit of quantification (LLOQ: 20-50 copies/ml) and to determine the odds of virological success at 52 weeks associated with single and consecutive pVL rebounds.A group of 165 patients achieved a pVL nadirLLOQ; of these, 85 patients experienced pVL rebounds within 52 weeks. The probability of a pVL rebound was greater among patients who did not adhere to treatment (68% vs 49%; P0.05). The probability of reachieving virological suppression after a pVL rebound was not associated with the magnitude of the rebound [odds ratio (OR), 0.86; P = 0.56] but was associated with triple therapy (OR, 2.22; P = 0.06) or non-adherence (OR, 0.40; P = 0.04). The probability of virological success at week 52 was not associated with an isolated pVL rebound but was less likely after detectable pVL at two consecutive visits.An isolated pVL rebound was not associated with virological success at 52 weeks but rebounds at two consecutive visits decreased the probability of later virological success. Given their high risk of short-term virological failure, patients who present with consecutive detectable pVL measurements following complete suppression should be considered ideal candidates for intervention studies.

In this study, changes in plasma virus load, peripheral blood CD4 T cell counts and the T cell repertoire were assessed in eight chronically HIV-infected individuals suspending antiretroviral therapy. Despite rapid increases in virus load and substantial CD4 T cell losses during treatment interruption, no marked changes in the T cell receptor beta chain repertoire were observed. The magnitude of associated T cell repertoire perturbation thus contrasts with that observed during primary HIV infection.

Objective To describe clinical experience with atovaquone suspension for the treatment of Pneumocystis carinii pneumonia (PCP) in HIV-infected patients. Design A retrospective chart review. Methods The medical records of 54 HIV-infected patients with PCP treated with atovaquone were examined. The outcomes of 34 patients treated with atovaquone suspension (750 mg twice a day) were compared with those of 20 patients treated with atovaquone tablets (750 mg three times a day). Results The proportion of patients successfully treated was similar with the suspension (74%) and tablet (70%) formulations of atovaquone. The proportion of patients with an inadequate response to therapy was lower for patients treated with atovaquone suspension (15%) than tablets (30%). Both formulations were well tolerated. Conclusion Atovaquone suspension is effective and well tolerated for the treatment of PCP.

Objective To model the potential impact of HIV infection rates and the use of antiretroviral medication on life expectancy and mortality in the Downtown Eastside of Vancouver, British Columbia, Canada, from 1999 to 2006. Design Population projections were made to estimate the population of the Downtown Eastside in the year 2006. Methods Two scenarios were modelled to predict the impact of HIV infection and antiretroviral use on mortality and life expectancy. The use of antiretroviral therapy was estimated to be 80% in the first scenario and 20% in the second. The prevalence of HIV by age and sex, and by year infected was estimated using data from the Vancouver Injection Drug User Study. Results If the level of antiretroviral therapy use among HIV-positive individuals was 80% at baseline, then we estimate that the life expectancy at birth in the year 2006 will be 60.8 years for men and 72.8 years for women, and 172 AIDS deaths will occur between 1999 and 2006. In contrast, if the present level of antiretroviral medication use persists, the life expectancy at birth in the year 2006 will be 56.9 years for men and 68.6 years for women, and 503 AIDS deaths will occur between 1999 and 2006. Conclusion Our analysis suggests that if the low levels of antiretroviral therapy use persist, life expectancy in Vancouver's Downtown Eastside will soon be on a par with many of the world's least developed countries. Our findings highlight the large health status decline that can be expected in many inner city neighbourhoods if low levels of antiretroviral use persist. Although reasonable coverage targets for injection drug users (IDU) have not been established, the expanded use of antiretroviral medication is urgently needed to avert a drastic decline in health status.

Objective To determine the rate of plasma HIV-1 RNA rebound in patients stopping highly active antiretroviral therapy (HAART) after achieving undetectable viral load. Design Sequential plasma HIV RNA levels were measured in six patients during the 21 days following withdrawal from HAART. Methods Plasma samples were obtained from six patients who chose to withdraw from HAART because of lipodystrophy, narcotic overdose, insomnia and/or high blood pressure. Longitudinal plasma viral load was determined in triplicate upon stopping therapy. Results All patients had plasma viral loads below 50 HIV RNA copies/ml at the time of stopping therapy and had had levels below 500 copies/ml for a median of 390 days (range 39-542 days). Plasma HIV rebound upon stopping therapy was rapid (median increase 0.2 log/day; range 0.15-0.42 log/day) and initially appeared to follow first-order kinetics. Plasma HIV RNA levels returned to greater than 500 copies/ml within 6 to 15 days (median 10 days) and approached or exceeded pre-therapy levels in all patients within 21 days of stopping therapy. Extrapolating backwards to the time at which individuals stopped therapy suggested that patients had tens of thousands of total body plasma HIV RNA copies despite having 'undetectable' plasma HIV RNA. Conclusions HIV RNA in plasma rebounds within days of stopping antiretroviral therapy. A considerable burden of total body plasma HIV RNA likely remains even during effective HAART therapy.

To estimate the potential direct cost of making triple combination antiretroviral therapy widely available to HIV-positive adults and children living in countries throughout the world.For each country, antiretroviral costs were obtained by multiplying the annual cost of triple antiretroviral therapy by the estimated number of HIV-positive persons accessing therapy. Per capita antiretroviral costs were computed by dividing the antiretroviral costs by the country's total population. The potential economic burden was calculated by dividing per capita antiretroviral costs by the gross national product (GNP) per capita. All values are expressed in 1997 US dollars.The potential cost of making triple combination antiretroviral therapy available to HIV-positive individuals throughout the world was estimated to be over US$ 65.8 billion. By far the greatest financial burden was on sub-Saharan Africa. The highest per capita drug cost in this region would be incurred in the subregions of Southern Africa (US$ 149) followed by East Africa (US$ 116), Middle Africa (US$ 44), and West Africa (US$ 42). In the Americas, subregional data indicated the highest per capita drug cost would be in the Latin Caribbean (US$ 22), followed by the Caribbean (US$ 17), Andean Area (US$ 7), the Southern Cone (US$ 6), North America (US$ 6), and Central American Isthmus (US$ 5). In Asia and Europe the percentage of the GNP necessary to finance drug therapy was less than 1% in most countries examined.Our results demonstrate that the cost of making combination antiretroviral therapy available worldwide would be exceedingly high, especially in countries with limited financial resources.In 1997, an estimated 5.8 million people worldwide were infected with HIV, of whom 90% lived in developing countries, especially in sub-Saharan Africa. While antiretroviral therapy has been shown to prolong survival in people with HIV/AIDS, many of the countries with the highest rates of HIV infection have little or no access to antiretroviral therapy, for a number of reasons, including cost. Findings are presented from a study conducted to estimate the potential direct cost of making triple combination antiretroviral therapy widely available to all of the world's HIV-infected population. The potential cost of making such therapy available to HIV-positive people worldwide was estimated to be over US$65.8 billion, in 1997 US dollars, with the greatest expenditures needed in sub-Saharan Africa. The highest per capita drug cost in sub-Saharan Africa would be incurred in Southern Africa (US$149), followed by East Africa (US$116), Middle Africa (US$44), and West Africa (US$42). In the Americas, per capita drug costs would be US$22 in the Latin Caribbean, US$17 in the Caribbean, US$7 in the Andean Area, US$6 in the Southern Cone and North America, and US$5 in the Central American Isthmus. In Europe and Asia, the percentage of GNP needed to finance drug therapy was less than 1% in most countries examined. For each country, antiviral costs were determined by multiplying the annual cost of triple antiretroviral therapy by the estimated number of HIV-positive people accessing therapy. Per capita therapy costs were calculated by dividing the antiretroviral costs by the country's total population. The potential economic burden was calculated by dividing per capita antiretroviral costs by the gross national product (GNP) per capita.

Objective To determine the value of plasma HIV-1 RNA and CD4 cell count as predictors of the clinical benefit of antiretroviral treatment. Design and setting The CAESAR (Canada, Australia, Europe, South Africa) trial randomized 1840 patients [inclusion CD4 cell count, 25-250 x 10(6)/l] to add either placebo, lamivudine (3TC) or 3TC plus loviride in a double-blinded fashion to baseline treatments (zidovudine, zidovudine-didanosine or zidovudine-zalcitabine) for 1 year. Patients This analysis included 487 patients with data on CD4 cell count and HIV-1 RNA after 12-20 weeks of treatment and subsequent follow-up for clinical progression. Main outcome measures The correlation between 12-20-week change in CD4 cell count, HIV-1 RNA and progression to AIDS or death in the placebo group was used to predict the clinical benefit of the 3TC-containing arms of the trial, given their effects on CD4 cell count and HIV-1 RNA. Results After 12-20 weeks of treatment, HIV-1 RNA fell by 0.37 log10 copies/ml in the 3TC arms versus a rise of 0.05 log10 copies/ml in the placebo arm. The 12-20-week CD4 cell count rose by 35 x 10(6)/l in the 3TC arm versus a fall of 8 x 10(6)/l in the placebo arm. After 12-20 weeks of treatment, a reduction in HIV-1 RNA of 1 log10 at 12-20 weeks predicted a 49% reduction in progression [hazard ratio (HR), 0.51; 95% confidence interval (CI), 0.30-0.87] and a rise in CD4 cell count of 50 x 10(6)/l predicted a 51% reduction in progression (HR, 0.49; 95% CI, 0.33-0.73). Using the model from the placebo arm, the rises in CD4 cell count and reductions in HIV-1 RNA during 3TC treatment predicted a 59% reduction in progression to AIDS or death. The observed clinical benefit was a 57% reduction in progression for the 3TC arms versus placebo (HR, 0.43; 95% CI, 0.26-0.71). Conclusions Rises in CD4 cell count and reductions in HIV-1 RNA were reliable in predicting the clinical benefit of 3TC in the CAESAR trial.

To describe prevalence and incidence of HIV-1, hepatitis C virus (HCV) and risk behaviours in a prospective cohort of injecting drugs users (IDU).Vancouver, which introduced a needle exchange programme (NEP) in 1988, and currently exchanges over 2 million needles per year.IDU who had injected illicit drugs within the previous month were recruited through street outreach. At baseline and semi-annually, subjects underwent serology for HIV-1 and HCV, and questionnaires on demographics, behaviours and NEP attendance were completed. Logistic regression analysis was used to identify determinants of HIV prevalence.Of 1006 IDU, 65% were men, and either white (65%) or Native (27%). Prevalence rates of HIV-1 and HCV were 23 and 88%, respectively. The majority (92%) had attended Vancouver's NEP, which was the most important syringe source for 78%. Identical proportions of known HIV-positive and HIV-negative IDU reported lending used syringes (40%). Of HIV-negative IDU, 39% borrowed used needles within the previous 6 months. Relative to HIV-negative IDU, HIV-positive IDU were more likely to frequently inject cocaine (72 versus 62%; P0.001). Independent predictors of HIV-positive serostatus were low education, unstable housing, commercial sex, borrowing needles, being an established IDU, injecting with others, and frequent NEP attendance. Based on 24 seroconversions among 257 follow-up visits, estimated HIV incidence was 18.6 per 100 person-years (95% confidence interval, 11.1-26.0).Despite having the largest NEP in North America, Vancouver has been experiencing an ongoing HIV epidemic. Whereas NEP are crucial for sterile syringe provision, they should be considered one component of a comprehensive programme including counselling, support and education.

To estimate and compare the societal impact of HIV infection and AIDS with other selected causes of male mortality in terms of the indirect costs of future production lost.Descriptive, population-based economic evaluation study.All men aged 25-64 years for whom HIV/AIDS or another selected disease was listed as the underlying cause of death in Canada from 1987 to 1991, as reported to Statistics Canada.Canada.Present value of future earnings lost for men using a human capital approach based on potential years of life lost in men aged 25-64 years.Assuming a 2% annual growth in earnings and a 3% annual real discount rate, the present value of the total loss of future production for all men aged 25-64 years who died in Canada during 1987-1991 was estimated to be 39.74 billion 1990 US$. Deaths due to HIV/AIDS accounted for 5.3% of this total loss or 2.11 billion in 1990 US$. Future production loss due to HIV/AIDS more than doubled during the period from 1987 to 1991, from 0.27 to 0.60 billion 1990 US$. The loss in future earnings attributable to HIV/AIDS was exceeded only by that of ischaemic heart disease (15.2%), suicide (9.4%), motor vehicle accidents (6.6%), and lung cancer (6.6%). In total, these five causes of death accounted for 43.1% of the total indirect cost of production lost for men aged 25-64 years during the 5-year period.Our findings demonstrated HIV/AIDS mortality is already having a dramatic impact on future wealth production in Canada. If the past trend continues, the production lost in 1994 should exceed 0.86 billion 1990 US$ and will account for more than 10% of the total annual loss for men aged 25-64 years.

OBJECTIVE To describe the changing spectrum of AIDS index diseases in Canada over a 10-year period from 1981 to 1991. DESIGN A descriptive, population-based study. SETTING Canada. PATIENTS All cases of AIDS in Canada reported by the Division of HIV/AIDS Epidemiology of the Department of National Health and Welfare. MAIN OUTCOME MEASURES Age-standardized rates of initial AIDS manifestations (1987 Centers for Disease Control and Prevention case definition), by year of diagnosis among adults in Canada. RESULTS A total of 6641 adult AIDS cases were examined. The rate of Pneumocystis carinii pneumonia (PCP) peaked in 1989 with a rate of 3.18 per 100,000, declining to 2.74 per 100,000 in 1991 (P = 0.894). Similarly, the rate of Kaposi's sarcoma (KS) stabilized during this interval from 1.06 per 100,000 in 1987 to 1.14 per 100,000 in 1991 (P = 0.189). In contrast, the rates of all other AIDS-defining illnesses increased from 1.48 per 100,000 in 1987 to 3.43 per 100,000 in 1991 (P = 0.001). For these other AIDS index diseases, significant rate increases were observed for esophageal candidiasis, cytomegalovirus (CMV) diseases, wasting syndrome, toxoplasmosis, and Mycobacterium avium complex (MAC) disease. CONCLUSIONS Our study shows a leveling and decline in incidence of KS and PCP, respectively, and a concomitant increase of other diagnoses, especially esophageal candidiasis, CMV, wasting syndrome, toxoplasmosis, and MAC disease in Canada. These findings highlight the importance of developing specific strategies to prevent emerging AIDS index diseases and serve as a cautionary note to practicing clinicians, indicating the relative widening of the spectrum of HIV index diseases.

Objective Validation of a modified version of the recently proposed World Health Organization (WHO) staging system for HIV infection and disease in a cohort of homosexual men. Methods Five hundred and thirty HIV-positive men followed for a median of 51 months (range, 1–98 months) were eligible for analysis. Subjects were classified into stages at their first seropositive visit and at all subsequent visits. Results As of 1 April 1991, 136 subjects (26%) had progressed to stage IV of the modified WHO system on the basis of their CD4 lymphocyte counts, and 78 subjects (15%) had died. Kaplan-Meier estimates for progression to stage IV from stages I, II and III were 52.8 ± 7.5% over 6.6 years, 58.1 ± 7.1% over 5.9 years and 66.5 ± 9.7% over 5.7 years (log-rank P = 0.0001). Estimated median times to stage IV were 6.4, 5.3 and 3.8 years from stages I, II and III, respectively. Estimated median times to death were 10.9, 8.2, 6.3 and 1.7 years from stages I to IV, respectively. Results remained unchanged when CD4 lymphocyte count was replaced with lymphocyte count in the laboratory axis of the staging system. Conclusions The proposed staging scheme, based on the WHO system, provides a prognostically meaningful classification for HIV infection in a cohort of homosexual men. Furthermore, the use of absolute lymphocyte count as a valid alternative for CD4 lymphocyte count has implications for the applicability of this system in many parts of the world where diagnostic resources are limited.

During 1989, 316 members of a cohort of homosexual men were tested for HIV-specific DNA by the polymerase chain reaction (PCR) using a pair of gag-region primers. Of 125 HIV-seronegative subjects, 123 (98.4%) were PCR-negative while 158 (82.7%) of 191 HIV-seropositive subjects were PCR-positive. Fewer of the 33 subjects who were seropositive and PCR-negative were at Centers for Disease Control (CDC) stage IV than the seropositive, PCR-positive subjects (6 versus 25%; P = 0.030). The seropositive, PCR-negative group had higher mean CD4 counts (640 versus 490 x 10(6) cells/l; P = 0.006), higher CD4: CD8 ratios (0.92 versus 0.64; P = 0.004), lower immunoglobulin (Ig) G levels (1290 versus 1645 mg/dl; P = 0.002), lower IgA levels (168 versus 251 mg/dl; P less than 0.001), and lower C1q binding activity (8 versus 14%; P = 0.010) than the seropositive, PCR-positive subjects. The median rate of CD4 cell decline in the 3 years preceding the PCR sample was less marked in the seropositive, PCR-negative group than the seropositive, PCR-positive group (-58 versus -77 x 10(6) cells/l per year; P = 0.028). To control for duration of infection, we restricted the analysis to the subgroups of 11 seropositive, PCR-negative subjects and 34 seropositive, PCR-positive subjects who had seroconverted earlier in the cohort study. Both subgroups had similar durations of infection, yet the same pattern of differences persisted.(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate whether predictors of AIDS progression are operative very early in the natural history of HIV infection, we conducted a nested case-control study within a cohort of 119 subjects who seroconverted while under observation in a prospective study of homosexual men. For each of the 18 cases who have progressed to AIDS, we randomly selected three controls who had seroconverted within 3 months of the case but who have remained AIDS-free. Cases and controls were compared with regard to laboratory and clinical parameters obtained at the time of the earliest HIV-positive result. The median duration between the estimated date of seroconversion and this first positive result was 4 months for cases and 6 months for controls. Cases exhibited lower CD4 counts (657 versus 774 x 10(6)/l; P = 0.037), lower CD4: CD8 ratios (0.98 versus 1.39; P = 0.003), higher immune complex levels (C1q binding: 25 versus 15%; P = 0.002), lower hemaglobin concentrations (14.8 versus 15.2 g/l; P = 0.011), higher immunoglobulin (Ig) A levels (272 versus 184 mg/dl; P = 0.003), and higher IgG levels (1530 versus 1300 mg/dl; P = 0.037) than controls. Cases exhibited higher CD8 counts of marginal statistical significance (732 versus 597 x 10(6)/l; P = 0.059). No differences were observed with respect to IgM levels, total lymphocyte or white blood cell counts, or the frequency of generalized lymphadenopathy. A total of 27.8% of cases but only 11.5% of controls reported one or more symptoms during the 6-month period preceding the first positive visit (P = 0.027). We conclude that laboratory and clinical abnormalities which are predictive of more rapid progression to AIDS may appear very early in HIV infection. This suggests that some of the factors responsible for more rapid disease progression are present in the host prior to or shortly after infection occurs.

As part of an ongoing prospective study of seropositive homosexual men in Vancouver, Canada, a seroprevalent cohort of 246 subjects (i.e. duration of infection unknown) and a seroincident cohort of 102 subjects (i.e. duration of infection known) were followed a median of 63 and 45 months, respectively. Follow-up with validation utilizing record linkage with the Canadian Federal Centre for AIDS registry revealed 58 and nine cases of AIDS in the seroprevalent and seroincident cohorts, respectively, through July 1988. These data yield product limit estimates of the cumulative progression rates to AIDS at 60 months of 23.0% for the seroprevalent cohort, 13.0% for the seroincident cohort, and 21.0% for the combined groups. Univariate analyses revealed the following to be statistically and clinically significant predictors of AIDS progression: low CD4 counts, low CD4/CD8 ratios, elevated immune complexes, elevated immunoglobulin G (IgG) and immunoglobulin A (IgA) levels, and low platelet counts. Cox regression revealed that elevated IgA levels, low CD4 counts, elevated immune complexes, two or more symptoms, and more than 20 male sexual partners in high-risk areas in the 5 years prior to enrollment were independent predictors of progression to AIDS over the subsequent 5 years. A multivariate risk function based on the latter five variables delineated low-, medium- and high-risk groups whose 5-year progression rates to AIDS were 6.7, 15.6 and 64.4%, respectively. The high-risk group contained 75% of all subjects who progressed to AIDS. Only 6% of the high-risk group would have qualified for zidovudine therapy under current guidelines at the beginning of the observation period.(ABSTRACT TRUNCATED AT 250 WORDS)