Deadly public policy: what the future could hold for the HIV epidemic among injection drug users in Vancouver.

The scope and scale of the HIV outbreak that occurred among injection drug users in Vancouver in the late 1990s was unprecedented and resulted in some 2,000 new HIV infections, with incidence rates reaching 18 per 100 person-years. This outbreak, localized mainly in one neighbourhood, cost the Canadian health care system more than 1 billion dollars to diagnose, care and treat. A number of factors combined to stabilize HIV incidence: 1) HIV prevalence became saturated among those at highest risk; 2) several public health policies focused on drug users were implemented, including increased and additional decentralized needle exchange programs, expanded methadone maintenance services, better addiction treatment services, improved housing, and mental health programs; and 3) increased access and expansion of Highly Active Antiretroviral Therapy. To ensure that a similar outbreak never occurs again in Vancouver and other cities, future health policy must consider the political, psychosocial and socioeconomic factors that contributed to this outbreak. These policies must address the unintended adverse consequences of past policies and their repercussions for marginalized individuals living in this community and beyond.

Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients.

BACKGROUND: Nucleoside analogues can induce toxic effects on mitochondria by inhibiting the human DNA polymerase gamma. The toxic effects can range from increased serum lactate levels to potentially fatal lactic acidosis. We studied changes in mitochondrial DNA relative to nuclear DNA in the peripheral-blood cells of patients with symptomatic, nucleoside-induced hyperlactatemia. METHODS: Total DNA was extracted from blood cells. A nuclear gene and a mitochondrial gene were quantified by real-time polymerase chain reaction. Three groups were studied: 24 controls not infected with the human immunodeficiency virus (HIV), 47 HIV-infected asymptomatic patients who had never been treated with antiretroviral drugs, and 8 HIV-infected patients who were receiving antiretroviral drugs and had symptomatic hyperlactatemia. The patients in the last group were studied longitudinally before, during, and after antiretroviral therapy. RESULTS: Symptomatic hyperlactatemia was associated with marked reductions in the ratios of mitochondrial to nuclear DNA, which, during therapy, averaged 68 percent lower than those of non-HIV-infected controls and 43 percent lower than those of HIV-infected asymptomatic patients never treated with antiretroviral drugs. After the discontinuation of antiretroviral therapy, there was a statistically significant increase in the ratio of mitochondrial to nuclear DNA (P=0.02). In the patients followed longitudinally, the decline in mitochondrial DNA preceded the increase in venous lactate levels. CONCLUSIONS: Mitochondrial DNA levels are significantly decreased in patients with symptomatic, nucleoside-related hyperlactatemia, an effect that resolves on the discontinuation of therapy.

Effect of medication adherence on survival of HIV-infected adults who start highly active antiretroviral therapy when the CD4+ cell count is 0.200 to 0.350 x 10(9) cells/L.

BACKGROUND: The safety of delaying highly active antiretroviral therapy (HAART) in HIV-infected patients is uncertain when the CD4+ cell count declines below 0.350 x 10(9) cells/L. OBJECTIVE: To evaluate the effect of baseline CD4+ cell count and adherence to HAART on survival rates. DESIGN: Prospective observational study. SETTING: Province-wide Canadian HIV/AIDS treatment program. PATIENTS: 1422 HIV-infected persons initiating HAART between 1 August 1996 and 31 July 2000 and followed through 31 March 2002. MEASUREMENTS: Patients were stratified by baseline CD4+ cell count and adherence level. Cumulative mortality rates were evaluated by using Kaplan-Meier methods and Cox regression-estimated adjusted relative hazards. RESULTS: Kaplan-Meier analyses showed no survival benefit of starting HAART at a CD4+ count of 0.200 x 10(9) cells/L or greater among adherent patients. Adjusted analysis showed that compared with adherent patients who initiated HAART at a CD4+ cell count of 0.350 x 10(9) cells/L or greater, nonadherent patients who initiated HAART when the CD4+ cell count was 0.200 to 0.349 x 10(9) cells/L had statistically elevated mortality rates (adjusted relative hazard, 2.56 [95% CI, 1.36 to 4.84]; P = 0.004). However, compared with adherent patients who initiated HAART at a CD4+ cell count of 0.350 x 10(9) cells/L or greater, adherent patients who initiated HAART when the CD4+ cell count was 0.200 to 0.349 x 10(9) cells/L had statistically similar mortality rates (adjusted relative hazard, 0.82 [CI, 0.45 to 1.49]; P > 0.2). CONCLUSIONS: Delaying HAART until the CD4+ cell count falls to 0.200 x 109 cells/L does not increase the mortality rate in HIV-infected patients with good medication adherence. Mortality rates increase if HAART is initiated below 0.200 x 10(9) cells/L. Also, nonadherent patients have higher mortality rates than adherent patients with similar CD4+ cell counts. Above a CD4+ cell count of 0.200 x 10(9) cells/L, medication adherence is the critical determinant of survival, not the CD4+ cell count at which HAART is begun.

Provider bias in the selection of non-nucleoside reverse transcriptase inhibitor and protease inhibitor-based highly active antiretroviral therapy and HIV treatment outcomes in observational studies.

OBJECTIVE: To compare the characteristics of patients prescribed non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI), and evaluate treatment outcomes in a setting in which nevirapine has been preferentially recommended since 1998. METHODS: A population-based analysis of antiretroviral-naive adults who started highly active antiretroviral therapy (HAART) between 1 August 1996 and 31 July 2000, and who were followed until 31 March 2002. We compared baseline characteristics, and evaluated virological responses and mortality. RESULTS: Overall, 439 patients (28.8%) started HAART with NNRTI (94.1% used nevirapine), 100 (6.6%) used a double PI, and 983 (64.6%) used a single PI-based regimen. Substantial differences were observed between the baseline clinical characteristics of these populations. In adjusted analyses, in comparison with single PI therapy, only the use of NNRTI was associated with more rapid HIV-RNA suppression [relative hazard (RH) 1.42; 95% confidence interval (CI) 1.22-1.65; P < 0.001]. A total of 204 deaths were identified in the study population [42 (9.6%) NNRTI; 11 (11%) double PI; 151 (15.4%) single PI, respectively]. In adjusted analysis, NNRTI (RH 1.01; 95% CI 0.71-1.45) and double PI-based HAART (RH 0.74; 95% CI 0.40-1.39) had similar mortality rates to the single PI reference category. CONCLUSION: NNRTI use was associated with more rapid virological suppression, whereas similar rates of rebound and mortality were found. Nevertheless, major baseline differences existed between patients prescribed the various initial regimens. As such, it is likely that similar selection factors may explain why our findings contrast with several non-randomized studies showing worse clinical outcomes of patients prescribed nevirapine.

Intermittent use of triple-combination therapy is predictive of mortality at baseline and after 1 year of follow-up.

OBJECTIVE: To characterize the impact of intermittent use of triple drug antiretroviral therapy on survival. DESIGN, SETTING AND PARTICIPANTS: Population-based analysis of 1282 antiretroviral therapy naive HIV-positive individuals aged 18 years and older in British Columbia who started triple-combination therapy between August 1996 and December 1999. Therapy use was estimated by dividing the number of months of medications dispensed by the number of months of follow-up. Intermittent therapy was defined as the participant having obtained less than 75% of their medication in the first 12 months. MAIN OUTCOME MEASURE: Cumulative all-cause mortality rates from the start of triple drug antiretroviral therapy to 30 September 2000. RESULTS: As of 30 September 2000, 106 subjects had died. Cumulative mortality was 3.9% (+/- 0.5%) at 12 months. In a multivariate model, after controlling for other variables that were significant in the univariate analyses each 100 cell decrement in baseline CD4 cell count and the intermittent use of antiretroviral drugs were associated with increased mortality with risk ratios of 1.31 [95% confidence interval (CI), 1.16-1.49; P < 0.001] and 2.90 (95% CI, 1.93-4.36; P < 0.001), respectively. In order to control for downward drift, intermittent use of therapy was measured over the first year whereas other factors were measured at the end of year 1. After adjusting for all other factors, those participants who used antiretroviral drugs intermittently were 2.97 times (95% CI, 1.33-6.62; P = 0.008) more likely to die. CONCLUSION: Our study demonstrates that even after adjusting for other prognostic factors intermittent use of antiretroviral therapy was associated with increased mortality.

Prescribing practices in a population-based HIV postexposure prophylaxis program.

OBJECTIVES: To characterize factors associated with being prescribed triple or double postexposure prophylaxis (PEP) against HIV in a population-based program. METHODS: Individuals potentially exposed to HIV received a 5 day starter kit of either double or triple antiretroviral PEP between April 1999 and November 2000 and did/did not receive the remaining 23 days PEP. Data were collected through dispensation of kits. Logistic regression identified characteristics independently associated with being prescribed triple therapy starter kits and with any 23 day follow-up. RESULTS: Of 2064 people receiving 5 day PEP [403 (20%) triple and 1661 (80%) double], 590 (29%) received 23 day follow-up. Independently associated with being prescribed triple therapy starter kits were being male [adjusted odds ratio (AOR) 1.38; 95% confidence interval (CI) 1.10-1.74; P = 0.006), occupational mucocutaneous injuries (AOR 1.70; 95% CI, 1.14-2.55; P = 0.010), and community needlesticks (AOR 2.04; 95% CI, 1.54-2.69; P < 0.001). Independently associated with being prescribed the 23 day follow-up were being male (AOR 1.24; 95% CI, 1.00-1.53; P = 0.04), community mucocutaneous incidents (AOR 2.83; 95% CI, 1.41-5.70; P = 0.004), community needlesticks (AOR 1.75; 95% CI, 1.33-2.29; P < 0.001), and having received triple therapy as the starter kit (AOR 2.61; 95% CI, 2.07-3.29; P < 0.001). CONCLUSIONS: Being prescribed triple therapy starter PEP was associated with being male and with experiencing an occupational mucocutaneous or community needlestick injury. Receiving the remaining 23 days PEP was associated with being male, experiencing a community mucocutaneous or needlestick injury, and triple therapy as the initial 5 day starter PEP.

Factors associated with persistent high-risk syringe sharing in the presence of an established needle exchange programme.

Vancouver has experienced an explosive HIV epidemic despite the presence of a needle exchange programme (NEP). We sought possible explanations for high-risk syringe sharing among Vancouver injection drug users over the period January 1999 to October 2000. Overall, 14% of participants reported high-risk sharing. Although acquiring needles exclusively from the NEP was independently associated with less sharing, we identified several risk factors for persistent sharing, including difficulty accessing sterile needles, bingeing, and frequent cocaine injection.

Socioeconomic status, access to triple therapy, and survival from HIV-disease since 1996.

BACKGROUND: In the era before highly active antiretroviral therapy (HAART), socioeconomic status was associated with survival from HIV disease. We have explored socioeconomic status, access to triple therapy (HAART), and mortality in the context of a universal healthcare system. METHODS: We evaluated 1408 individuals who initiated double or triple therapy between 1 August 1996 and 31 December 1999, and were followed until 31 March 2000. Cumulative HIV-related mortality rates were estimated using Kaplan-Meier methods and Cox proportional hazards regression. RESULTS: In the overall Cox model, we found that adherence [risk ratio (RR) 0.83; per 10% increase], CD4 cell count (RR 1.53; per 100 cell decrease), and lower socioeconomic status (RR 2.19; high versus low), were associated with HIV-related mortality. However, socioeconomic status was not significant among patients prescribed triple therapy in a stratified analysis, or in a sub-analysis restricted to patients prescribed HAART in the initial regimen. When we investigated if inequitable access to HAART by socio-economic status could explain the discrepancy, we found that persons in the lower socio-economic strata were less likely to be prescribed triple therapy even after adjustment for clinical characteristics. CONCLUSION: In a universal healthcare system, socioeconomic status was strongly associated with HIV-related mortality. When we investigated possible explanations for this association, we found that individuals of lower socioeconomic status were less likely to receive triple therapy after adjustment for clinical characteristics. Our findings highlight the need for the monitoring of therapeutic guidelines to ensure equitable access, as treatment strategies are updated.

Is there a baseline CD4 cell count that precludes a survival response to modern antiretroviral therapy?

OBJECTIVE: Therapeutic guidelines advise that 200-350 x 106 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 x 106 cells/l the adjusted relative hazard of mortality was 5.07 [95% confidence interval (CI), 2.50-10.26] for patients of experienced physicians and was 11.99 (95% CI, 6.33-22.74) among patients with inexperienced physicians, in comparison to patients with > or = 200 x 106 cells/l treated by experienced physicians. Similarly, among patients with < 50 x 106 cells/l, the adjusted relative hazard of mortality was 6.19 (95% CI, 3.03-12.65) for adherent patients and was 35.71 (95% CI, 16.17-78.85) for non-adherent patients, in comparison to adherent patients with > or = 200 x 106 cells/l. CONCLUSION: Survival rates following the initiation of HAART are dramatically improved among patients starting with CD4 counts < 200 x 106 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 x 106 cells/l should be re-examined.

Influence of polymorphisms within the CX3CR1 and MDR-1 genes on initial antiretroviral therapy response.

OBJECTIVE: Single nucleotide polymorphisms (SNP) in the genes encoding the human CX3CR1 chemokine receptor and the P-glycoprotein multidrug transporter have been associated with accelerated disease progression in untreated individuals and implicated in therapeutic response, respectively. This retrospective study assessed the influence of SNP in the CX3CR1 and MDR-1 genes on initial virological and immunological response in 461 HIV-infected, antiretroviral-naive individuals initiating antiretroviral therapy in British Columbia, Canada. METHODS: CX3CR1 and MDR-1 SNP were determined by PCR amplification of human DNA from plasma, followed by DNA sequencing. Time to virological success [time to HIV plasma viral load (pVL) < or = 500 copies/ml], virological failure (subsequent time to the second of two consecutive pVL > or = 500) and immunological failure (time to the second consecutive CD4 cell count below baseline) were analyzed by Kaplan-Meier methods. RESULTS: Frequencies of CX3CR1 amino acid haplotypes were 249V 280T (0.75), 249I 280M (0.15), and 249I 280T (0.1). Frequencies of MDR-1 nucleotide polymorphisms were 3435C (0.47) and 3435T (0.53). There was no effect detected for SNP in CX3CR1 or MDR-1 on time to virological success, nor of CX3CR1 and MDR-1 SNP on time to virological and immunological failure, respectively ( P > 0.1). There was a trend to earlier virological failure in the MDR-1 3435C/C genotype group ( P = 0.07), and a statistically significant trend to earlier immunological failure in individuals with the CX3CR1 249I polymorphism ( P = 0.02). These remained significant after correcting for baseline age, sex, pVL, CD4 cell count, type of therapy, and adherence ( P < or = 0.05). CONCLUSION: Polymorphisms in MDR-1 and CX3CR1 may be associated with accelerated virological and immunological therapy failure, respectively.

Interventional cardiovascular procedures among HIV-infected individuals on antiretroviral therapy 1995-2000.

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% CI, 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.

No association between GB virus-C viremia and virological or immunological failure after starting initial antiretroviral therapy.

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 RNA as a positive control. Time to virological success [achieving HIV plasma viral load (pVL) < or = 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 CX CR1, 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.

Intensive injection cocaine use as the primary risk factor in the Vancouver HIV-1 epidemic.

OBJECTIVES: The explosive and ongoing injecting drug use-related HIV-1 epidemic in Vancouver continues to receive international attention. This study was conducted to determine how patterns of cocaine use influence the risk of HIV infection. METHODS: The Vancouver Injection Drug Users Study is an open prospective cohort of injecting drug users that began in May 1996. At enrollment and at semi-annual follow-up visits an interviewer administers a detailed semi-structured questionnaire. Cox proportional hazards models were used to determine behavioral and drug use patterns reported in the 6 months prior to HIV seroconversion. RESULTS: One-hundred and nine incident HIV infections have been observed during a mean follow-up of 31 months, from 940 HIV-seronegative participants. During the 6 months prior to seroconversion, predictors of HIV infection were injecting cocaine use [adjusted hazards ratio (AHR), 3.72], incarceration (AHR, 2.74), unstable housing (AHR, 2.36), methadone maintenance treatment (AHR, 1.98), and Aboriginal ethnicity (AHR, 1.78). Injecting cocaine use was predictive of HIV infection in a dose-dependent fashion. Compared with infrequent cocaine users, participants who averaged more than three injections per day were seven times more likely to contract HIV. In addition, the time to HIV infection was accelerated among regular cocaine injectors independent of concurrent heroin use. CONCLUSIONS: Injecting cocaine use was a strong, dose-dependent predictor of HIV seroconversion in this poly-drug using population. Injection cocaine users remain particularly vulnerable to HIV infection and treatment options for cocaine dependency remain woefully inadequate.

Nucleoside-related mitochondrial toxicity among HIV-infected patients receiving antiretroviral therapy: insights from the evaluation of venous lactic acid and peripheral blood mitochondrial DNA.

Nucleoside analogues inhibit human DNA polymerase gamma. As a result, they can produce mitochondrial toxicity. We evaluated the possible role of random venous lactic-acid determinations as a screening tool for mitochondrial toxicity among patients receiving nucleoside therapy. More recently, we have developed an assay that can detect changes in mitochondrial DNA (mtDNA) levels in peripheral blood cells. Using this assay, we have characterized changes in mtDNA relative to nuclear DNA (nDNA) in peripheral blood cells from patients with symptomatic nucleoside-induced hyperlactatemia. Our results demonstrated that symptomatic hyperlactatemia was associated with markedly low mtDNA : nDNA ratios. A statistically significant increase in the mtDNA : nDNA ratio was observed after the discontinuation of antiretroviral therapy. Full validation of monitoring the mtDNA : nDNA ratio is currently under way.

Highly active antiretroviral therapy: physician experience and enhanced adherence to prescription refill.

OBJECTIVE: To identify patient and physician characteristics that may act as determinants of adherence to prescription refill of triple combination antiretroviral therapy. METHODS: A population-based analysis of antiretroviral therapy-naive HIV-positive men and women in British Columbia, Canada, who initiated triple combination therapy between August 1 1996 and October 31 1998. Study participants were considered adherent if they were actually dispensed antiretrovirals > or = 95% over the first year of therapy. Log-binomial regression was used to identify patient and physician characteristics associated with adherence to prescription refill. RESULTS: Of the 886 individuals eligible for analysis, 495 (56%) were > or = 95% adherent to prescription refill. In multivariate analysis, adherence was positively associated with increased age [adjusted relative rate (ARR) 1.19; 95% CI: 1.07-1.32], having a diagnosis of AIDS (ARR 1.66; 95% CI: 1.29-2.15), being male (ARR 1.79; 95% CI: 1.27-2.53), and with greater experience of the treating physician (ARR 1.27; 95% CI: 1.13-1.42). History of injection drug use was negatively associated with adherence to prescription refill (ARR 0.65; 95% CI: 0.51-0.83), as was increased pill burden (per pill daily) (ARR 0.95; 95% CI: 0.92-0.99). A sub-analysis of 316 patients who provided additional data regarding psychosocial characteristics indicated that adherence was positively associated with physician experience (ARR: 1.28; 95% CI: 1.09-1.51) and being employed (ARR: 1.55; 95% CI: 1.14-2.21), and negatively associated with a history of injection drug use (ARR: 0.61; 95% CI: 0.43-0.85). CONCLUSION: While patient disease stage and personal characteristics may play an important role in patient adherence to prescription refill of complex therapeutic regimens, our findings indicate that HIV-experienced physicians may have greater success in maintaining patients on prescribed therapy.

Total lymphocyte count as a possible surrogate of CD4 cell count to prioritize eligibility for antiretroviral therapy among HIV-infected individuals in resource-limited settings.

OBJECTIVE: To characterize the value of total lymphocyte counts in predicting risk of death among patients initiating triple combination antiretroviral therapy. METHODS: Study subjects included antiretroviral-naive persons aged 18 years or older who initiated treatment with triple combination therapy between August 1 1996 and September 30 1999 in a population-based observational cohort of HIV-infected individuals. Total lymphocyte counts as well as CD4 count and plasma viral load were assessed at baseline. Separate Cox proportional hazards models were devised to evaluate the effect on survival of total lymphocyte count in lieu of or with CD4 count after adjustment for other prognostic factors including plasma viral load. RESULTS: A total of 733 antiretroviral-naive persons initiated triple drug combination antiretroviral therapy over the study period with a median follow-up of 29.5 months. In the first analysis, only baseline CD4 cell counts of 50-199 cells/microl or less than 50 microl were associated with an increased risk of mortality [adjusted relative risk (ARR) 2.90; 95% CI: 1.40, 5.98] and (ARR 6.30; 95% CI: 2.93, 13.54), respectively. When CD4 counts were excluded from the analysis as if unavailable, total lymphocyte count of between 0.8 and 1.4 G/I, and less than 0.8 G/I were both significantly associated with an increased risk of mortality (ARR 2.36; 95% CI: 1.16, 4.78) and (ARR 6.17; 95% CI: 2.93, 13.01), respectively. CONCLUSION: Total lymphocyte count may provide a simple and cost-effective alternative for prioritizing therapy initiation in resource-limited settings. Our results suggest that, if appropriately validated, judicious application of total lymphocyte counts could overcome one of the practical obstacles to more widespread provision of antiretroviral therapy in resource-poor settings.

Adherence to antiretroviral therapy and CD4 T-cell count responses among HIV-infected injection drug users.

OBJECTIVE: To evaluate the time to CD4 cell count response (> or = 50 cells/mm3) among patients initiating highly active antiretroviral therapy (HAART) with and without a history of injection drug use, and to examine the potential role of non-adherence to HAART on differential CD4 responses. METHODS: Population-based analysis of treatment-naive patients initiating HAART during the period 1 August 1996 to 31 July 2000 and who were followed until 31 March 2002. Patients were stratified based on 95% adherence and history of injection drug use, and Kaplan-Meier methods and Cox regression were used to evaluate CD4 response rates and factors associated with CD4 responses. RESULTS: Overall, the CD4 cell count response rate was slower among injection drug users in Kaplan-Meier analyses (log-rank: P<0.05). However, no differences existed when the analyses were restricted to adherent patients (log-rank: P=0.349). Similarly, the differences in the time to CD4 cell count response observed in univariate Cox regression analyses for patients with a history of injection drug use [relative hazard: 0.85 (95% CI: 0.75-0.97)] diminished after adjustment for adherence [adjusted relative hazard: 1.02 (95% CI: 0.89-1.16)]. CONCLUSION: These data demonstrate the importance of adherence on CD4 cell count responses and highlight the need for interventions to improve antiretroviral adherence among injection drug user.

Age, adherence and injection drug use predict virological suppression among men and women enrolled in a population-based antiretroviral drug treatment programme.

OBJECTIVES: To characterize 1-year virological response to antiretroviral therapy and its determinants by sex. METHODS: This is a population-based analysis of antiretroviral therapy naive HIV-positive adult men and women. Factors associated with sex and with plasma HIV RNA viral load suppression to below 500 copies/ml were examined using non-parametric tests and logistic regression analyses. RESULTS: A total of 739 subjects (92 women and 647 men) were eligible. Female participants were younger (34 vs 37 years; P < 0.001), less likely to have AIDS (6.5 vs 14.4%; P = 0.039), more frequently injection drug users (44.6 vs 25.2%; P = 0.001) and were less likely to be adherent to therapy (34.8 vs 62.9%; P < 0.001) than male participants. There was no difference in baseline median CD4 count (P = 0.424) or HIV RNA levels (P = 0.140), physician experience (P = 0.057), or with respect to antiretroviral regimens containing protease inhibitors or non-nucleoside reverse transcriptase inhibitors (P = 0.911). With treatment, 46.7% (43/92) of women and 64.8% (419/647) of men (P = 0.001) suppressed HIV RNA viral load to below 500 copies/ml at 1 year. In a multivariate analysis, the association of sex with HIV RNA response to antiretroviral therapy fell from statistical significance (odds ratio 1.18; 95% CI: 0.72-1.95) after adjusting for adherence, injection drug use and age. CONCLUSION: Our data indicate that in this population-based setting, sex differences in 1-year virological response to antiretroviral therapy are explained by age, adherence and injection drug use.

Prevalence and response to antiretroviral therapy of non-B subtypes of HIV in antiretroviral-naive individuals in British Columbia.

In North America, the B subtype of the major group (M) of HIV-1 predominates. Phylogenetic analysis of HIV reverse transcriptase and protease sequences isolated from 479 therapy-naive patients, first seeking treatment in British Columbia between June 1997 and August 1998, revealed a prevalence of 4.4% non-B virus. A range of different subtypes was identified, including one subtype A, 11 C, two D, five CRF01_AE, and one sample that could not be reliably subtyped. Baseline CD4 courts were significantly lower in individuals harbouring the non-B subtypes (P = 0.02), but baseline viral loads were similar (P = 0.80). In this study, individuals infected with non-B variants did not have a significantly different virological response to therapy after up to 18 months.

Modest decreases in NNRTI susceptibility do not influence virological outcome in patients receiving initial NNRTI-containing triple therapy.

OBJECTIVE: To assess the prevalence of modest (< 10-fold) decreases in baseline non-nucleoside reverse transcriptase inhibitor (NNRTI) susceptibility and their impact on virological response to NNRTI-containing triple therapy in drug-naive individuals. METHODS: Baseline HIV resistance phenotype, genotype and response to therapy were examined retrospectively for all antiretroviral-naive individuals initiating therapy with two nucleoside analogues and an NNRTI in British Columbia, Canada, between 05/1997 and 08/1999 (n = 279), followed until July 31 2001. Time to viral suppression (first of at least two consecutive plasma viral loads < 400 copies HIV RNA copies/ml) and viral rebound (to > or = 400 copies/ml after first pVL < 400 copies HIV RNA copies/ml), were estimated by Kaplan-Meier methods. Multivariate analyses were performed using Cox proportional hazards regression. RESULTS: Nevirapine was the most commonly prescribed NNRTI (96%). Four- to 10-fold decreased susceptibility to NNRTIs was observed in > 30% of untreated individuals at baseline, an observation strongly driven by decreased susceptibility to delavirdine (22.4%). A > 10-fold decrease in susceptibility to any NNRTI was observed only rarely (< 2%). There was no association between four- and 10-fold decreased baseline susceptibility to NNRTIs and virological outcome (P > 0.05). In multivariate analyses, the strongest predictors of poor virological response to NNRTI-based therapy were baseline plasma viral load and the proportion of time on therapy in the first year of follow-up. There was no relationship between the presence of previously reported mutations associated with decreased NNRTI susceptibility (at codons 135 and 283 in HIV reverse transcriptase) and virological response. CONCLUSIONS: These data suggest that the clinically significant level of resistance to NNRTIs, particularly nevirapine, in drug-naive individuals is likely greater than four- to 10-fold.