J. S. G. Montaner

Baseline HIV drug resistance profile predicts response to ritonavir-saquinavir protease inhibitor therapy in a community setting.

OBJECTIVE To determine whether baseline drug resistance assays could help to predict treatment failure with the protease inhibitor combination ritonavir-saquinavir. METHODS Baseline HIV-1 drug resistance was determined for 76 consecutive patients who started treatment with the dual protease inhibitor combination ritonavir-saquinavir between September 1996 and June 1997 either alone or in combination with other antiviral agents. Resistance to 10 different antiviral agents was assessed by both phenotype (Virco Antivirogram) and genotype (Vircogen). RESULTS Resistance inferred from viral genotype was similar to measured phenotypic resistance for both ritonavir and saquinavir (P<0.01). Baseline drug resistance phenotype was predictive of poor virological response to this dual protease inhibitor combination, despite the confounding effects of other antivirals. Patients were at least four times less likely to achieve a 0.5 log10 decrease in plasma HIV RNA viral load if their viral isolates were resistant to ritonavir or saquinavir. Patients classified as resistant to either drug using either method had median decreases in plasma viral load of 0.05 log10 HIV RNA copies/ml or less, compared to >0.8 log10 for those with sensitive virus. Patients resistant to both drugs never achieved plasma viral loads <100000 copies/ml. As little as fourfold increases in baseline resistance appeared to be sufficient to compromise even dual protease inhibitor therapy. CONCLUSION Baseline resistance to ritonavir or saquinavir or both was associated with a poor antiviral response. Our data suggest that the measurement of drug resistance may assist in optimizing antiretroviral therapy in the clinic.

Lower socioeconomic status and shorter survival following HIV infection

We studied the association between socioeconomic status and survival in a prospective study of 364 HIV-infected homosexual men who were recruited during 1982-84. The participants were divided by annual income; those earning above Canadian

Rectal gonorrhoea as an independent risk factor for HIV infection in a cohort of homosexual men.

10,000 (high-income; n = 274) and those below

High prevalence of food insecurity among HIV-infected individuals receiving HAART in a resource-rich setting

10,000 (low-income; n = 90) at recruitment. The latter threshold closely approximated to the poverty level for this population. Low income men were significantly younger than high income men but the groups were similar with respect to baseline CD4 counts, subsequent use of anti-retrovirals and prophylaxis against Pneumocystis carinii pneumonia (PCP), and number of visits attended during follow-up. Subjects were followed for a median of 9.5 years (range 1.8-13.1). By Dec 31, 1993, there were 135 deaths yielding a cumulative mortality rate of mean 45% (SD 4.0) at 11.5 years. Men aged 30 or more at infection had poorer survival than those under 30 (mortality risk ratio 1.56; 95% CI 1.09-2.24; p = 0.015), and longer survival was significantly associated with a higher CD4 count at the earliest seropositive visit. The age-adjusted mortality risk ratio for low income men compared with high income men was significantly increased at 1.63 (95% CI 1.11-2.40; p = 0.013). The significant risk of death for low income men persisted despite adjustment for age at infection, CD4 count, use of zidovudine, dideoxyinosine, and dideoxycytidine, use of PCP prophylaxis, and year of infection. We cannot attribute our findings to income loss as a result of more rapid HIV progression because the same effect was present in people who provided income data before seroconversion. Similarly, our findings are not due to differential access to care because the study was done within the context of a universal health care system, and the two income groups received treatments equally. This finding is consistent with the association of lower socioeconomic status with increased morbidity and mortality observed within large populations and in other diseases.

Prevalence of primary HIV drug resistance among seroconverters during an explosive outbreak of HIV infection among injecting drug users.

OBJECTIVE--To determine whether certain sexually transmitted diseases are independent risk factors for HIV transmission in a cohort of homosexual men. METHODS--Eligible cases were identified as those who had seroconverted between November 1982 and November 1990. Two persistently HIV-seronegative control participants were randomly selected for each case from all participants who remained seronegative in November 1990. For cases, risk factor data were taken from an index visit which was defined as the first seropositive visit, while for controls these data were obtained from a matched visit which occurred within two months of the index visit for the corresponding case. Mantel-Haenszel methods and logistic regression were used to compare differences in risk factors for seroconversion between cases and controls. RESULTS--A total of 125 cases and 250 controls were eligible for this study. Cases were significantly more likely to have had reported any gonorrhoea (17% versus 6%; OR = 2.94; 95% CI: 1.51-5.73) or syphilis (7% versus 2%; OR = 3.78; 95% CI: 1.33-10.79) than controls during the seroconversion period. Multivariate logistic regression revealed rectal gonorrhoea to be independently associated with risk of seroconversion (odds ratio = 3.18; p = 0.044), whereas urethral gonorrhoea (p = 0.479) and pharyngeal gonorrhoea (p = 0.434) were not after inclusion of rectal gonorrhoea. In addition, the following variables were also shown to exert an independent effect on seroconversion: frequency of anal intercourse, use of illicit drugs, number of male sexual partners, and lack of a post-secondary education. CONCLUSIONS--In this observational study, rectal gonorrhoea was found to be associated with HIV seroconversion after adjustment for a number of HIV risk factors. We cannot rule out that rectal gonorrhoea was not directly associated with HIV infection but rather with other residual lifestyle factors not fully adjusted for in the analysis. However, the relationship with gonococcal involvement of a specific anatomic site lends support to a biological association between gonorrhoea and HIV infection, rather than to alternative non-biologic explanations. Our findings are consistent with previous studies reporting an association between HIV infection and non-ulcerative sexually transmitted diseases. Such a direct association might be explained by postulating that gonorrhoea results in inflamed rectal mucosa and compromised epithelial integrity, thereby predisposing an individual to subsequent HIV infection.

Quality of life, depression and fatigue among persons co-infected with HIV and hepatitis C: Outcomes from a population-based cohort

Abstract This study aimed to assess the prevalence and correlates of food insecurity in a cohort of HIV-infected individuals on highly active antiretroviral therapy (HAART) in British Columbia (BC), Canada. Adults receiving HAART voluntarily enrolled into the Longitudinal Investigations into Supportive and Ancillary Health Services (LISA) cohort. Individual food insecurity was measured using a modified version of the Radimer/Cornell Questionnaire. We performed bivariate analyses to determine differences between explanatory variables for individuals who were food secure and food insecure. We performed logistic regression to determine independent predictors of food insecurity. Of the 457 individuals enrolled in the LISA cohort, 324 (71.0%) were found to be food insecure. Multivariate analysis indicated that individuals who had an annual incomes less than

The antiviral effect of ritonavir and saquinavir in combination amongst HIV-infected adults: results from a community-based study.

15,000 (odds ratio [OR] 3.15, 95% confidence interval [CI] 1.83, 5.44), used illicit drugs (OR 1.85, 95% CI 1.03, 3.33), smoked tobacco (OR 2.30, 95% CI 1.30, 4.07), had depressive symptoms (OR 2.34, 95% CI 1.38, 3.96), and were younger (OR 0.95, 95% CI, 0.92, 0.98) were more likely to be food insecure. Our results demonstrated a high (71%) prevalence of food insecurity among HIV-infected individuals receiving HAART in this resource-rich setting, and that food insecurity is associated with a compendium of environmental and behavioral factors. More research is needed to understand the biological and social pathways linking food insecurity to these variables in order to identify program strategies that can effectively improve food security among HIV-infected populations.

The changing spectrum of AIDS index diseases in Canada

OBJECTIVES This study examined the frequency of transmission of drug resistant HIV in the population of injecting drug users (IDU) in Vancouver, Canada during a period of particularly high virus transmission. DESIGN All subjects enrolled in the Vancouver Injection Drug Users Study who seroconverted from HIV negative to positive status (n = 61) between December 1996 and February 1998 were eligible for analysis. The first seropositive sample from 57 individuals with plasma samples available was analyzed for resistance to antiretroviral agents by population based sequencing of the HIV protease and reverse transcriptase genes. METHODS Plasma viral RNA was extracted and the viral reverse transcriptase and protease regions were amplified by nested reverse transcription-PCR. The presence of mutations associated with antiretroviral drug resistance was assessed by automated sequence analysis. RESULTS Protease and reverse transcriptase sequences were successfully obtained from the 57 recent seroconverters. No cases of transmission of variants associated with significant resistance to protease inhibitors or nucleoside and non-nucleosides reverse transcriptase inhibitors were detected. CONCLUSION The frequency of transmission of drug resistant HIV amongst these recently infected IDU is extremely low, with no protease or reverse transcriptase inhibitor resistant strains detected soon after seroconversion. The data provide no rationale for withholding treatment from this already marginalized population.

Drastic elevations in mortality among female injection drug users in a Canadian setting

The objective of the study was to describe the additional burden generated by hepatitis C (HCV) infection among HIV-infected individuals as measured by self-reported quality of life, depression and fatigue. The provincial HIV/AIDS Drug Treatment Program (DTP) distributes all antiretroviral medication in the province of British Columbia. Eligibility for accessing antiretrovirals is based on published guidelines commensurate with the International AIDS Society. Each participant is asked to complete a self-administered mailed questionnaire that includes patient sociodemographic information, quality of life measures (Medical Outcomes Study-Short Form (MOS-SF), mental health issues (Centre for Epidemiological Studies Depression scale (CESD) and fatigue information. HIV-HCV co-infected individuals were compared to HIV mono-infected individuals using parametric and nonparametric methods. Multivariate logistic regression was used to examine the impact of hepatitis C on quality of life, depression and fatigue, after controlling for sociodemographics and HIV-specific clinical characteristics. Of the 4,134 individuals who were sent a HIV/AIDS DTP survey in 1999, 2000 or 2001, 484 participants both returned one and had an HCV-antibody test result on file. Of the 484 participants eligible for this analysis, 105 (22%) were HCV-positive. In comparison to the 379 (78%) patients testing negative for HCV, a larger proportion of co-infected patients were female (18% versus 3%, p<0.001), aboriginal (20% versus 3%, p<0.001), had ever injected drugs (79% versus 5%, p<0.001), were unemployed (91% versus 49%, p<0.001) and lived in unstable housing (19% versus 1%, p<0.001) at the time they completed the survey. Co-infected patients reported more symptoms consistent with depression, increased fatigue and poorer quality of life. However, using multivariate modeling, it was determined that the impact of HCV on quality of life, depression and fatigue was better explained by the sociodemographic factors related to poverty and injection drug use, than by HCV itself. In conclusion, individuals co-infected with HIV and HCV represent a patient population with significant physical and mental health challenges. Although these patients experience poorer quality of life, increased depression and fatigue, this experience appears to be primarily related to socio-economic issues rather than HCV infection.

Inadequacies in antiretroviral therapy use among Aboriginal and other Canadian populations.

Objective:To characterize the antiviral effect and predictors of response to ritonavir and saquinavir-based antiretroviral combination therapy. Design:Intent-to-treat analysis with suppression of plasma viral load to levels below 2.7 log10 copies/ml as the main outcome measure. Patients:All adult HIV-positive individuals in the province of British Columbia who started taking ritonavir and saquinavir (each at 600 mg twice daily) in combination from 1 September 1996 to 28 February 1997, with a minimum of two plasma viral load measurements, one at baseline and one after the initiation of therapy. Results:A total of 58 participants were prescribed ritonavir and saquinavir. The median plasma viral load at entry was 4.80 log10 copies/ml (interquartile range, 4.51–5.15 log10 copies/ml). A total of 29 (50%) subjects demonstrated a decrease in plasma viral load to levels below 2.7 log10 copies/ml. This level of suppression was associated with higher baseline CD4 cell counts (P = 0.022) and no prior exposure to protease inhibitors (P = 0.001). After controlling for baseline CD4 cell count and plasma viral load, participants naive to protease inhibitors were almost seven times (odds ratio, 6.99; 95% confidence interval, 1.85–26.39; P = 0.004) more likely to suppress their plasma viral load to below 2.7 log10 copies/ml than those who had previously used protease inhibitors. Conclusion:Our analysis demonstrates that a ritonavir and saquinavir-based combination can produce a substantial decrease in plasma viral load with half of the participants decreasing their plasma viral load to below the limit of quantification of the assay. This response, however, is seriously compromised by prior exposure to protease inhibitors.