David R. Bangsberg

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.

Population-based community prevalence of methicillin-resistant Staphylococcus aureus in the urban poor of San Francisco

The study objective was to determine the prevalence and risk factors for nasal colonization with Staphylococcus aureus and methicillin resistance among the urban poor and to compare antibiotic resistance and genetic similarity to concurrently collected clinical isolates of methicillin-resistant S. aureus (MRSA). A population-based community sample of 833 homeless and marginally housed adults were cultured and compared with 363 clinical isolates of MRSA; 22.8% of the urban poor were colonized with S. aureus. Of S. aureus isolates, 12.0% were methicillin resistant. Overall prevalence of MRSA was 2.8%. Significant multivariate risk factors for MRSA were injection drug use (odds ratio [OR], 9.7), prior endocarditis (OR, 4.1), and prior hospitalization within 1 year (OR, 2.4). Resistance to antimicrobials other than beta-lactams was uncommon. Only 2 individuals (0.24%) with MRSA had no known risk factors. A total of 22 of 23 community MRSA genotypically matched clinical MRSA isolates, with 15 of 23 isolates identical to MRSA clones endemic among hospitalized patients.

A Simple, Dynamic Measure of Antiretroviral Therapy Adherence Predicts Failure to Maintain HIV-1 Suppression

BACKGROUND High levels of antiretroviral therapy adherence are important for human immunodeficiency virus type 1 (HIV-1) suppression, yet the magnitude of adherence required to maintain it is less well characterized. Furthermore, methods to accommodate changes in adherence over time are lacking. In the present study, our objective was to determine the magnitude of antiretroviral therapy adherence needed to maintain HIV-1 suppression by use of a time-updated adherence measure that has the potential to be of use in a clinical setting. METHODS We examined a population-based cohort of HIV-1-infected subjects > or =18 years of age, residing in British Columbia, Canada, who started receiving antiretroviral therapy between 1 August 1996 and 30 September 2003, who had at least 2 consecutive viral loads <500 copies/mL and who had prescriptions filled at least 3 times during a follow-up period ending 30 September 2004. Virological failure was defined as the second of 2 consecutive viral loads >1000 copies/mL. Cox proportional hazards model was used to determine the relationship between virological failure and refill-based, time-updated surrogate measure of adherence. RESULTS Among the 1634 participants > or =18 years of age who initiated triple combination therapy during the study, 606 virological failure events were identified. In multivariate analyses, subjects with < or =95% adherence were 1.66 (95% confidence interval, 1.38-2.01) times more likely to experience virological failure than those with >95% adherence. CONCLUSIONS The highest levels of antiretroviral therapy adherence are associated with higher rates of maintained virological suppression. This simple, dynamic surrogate measure of adherence overcomes the limitation of single-point-in-time calculations of adherence and may be useful in real time to determine whether an individual is exhibiting incomplete adherence.

Emergence of Drug Resistance Is Associated with an Increased Risk of Death among Patients First Starting HAART

Background The impact of the emergence of drug-resistance mutations on mortality is not well characterized in antiretroviral-naïve patients first starting highly active antiretroviral therapy (HAART). Patients may be able to sustain immunologic function with resistant virus, and there is limited evidence that reduced sensitivity to antiretrovirals leads to rapid disease progression or death. We undertook the present analysis to characterize the determinants of mortality in a prospective cohort study with a median of nearly 5 y of follow-up. The objective of this study was to determine the impact of the emergence of drug-resistance mutations on survival among persons initiating HAART. Methods and Findings Participants were antiretroviral therapy naïve at entry and initiated triple combination antiretroviral therapy between August 1, 1996, and September 30, 1999. Marginal structural modeling was used to address potential confounding between time-dependent variables in the Cox proportional hazard regression models. In this analysis resistance to any class of drug was considered as a binary time-dependent exposure to the risk of death, controlling for the effect of other time-dependent confounders. We also considered each separate class of mutation as a binary time-dependent exposure, while controlling for the presence/absence of other mutations. A total of 207 deaths were identified among 1,138 participants over the follow-up period, with an all cause mortality rate of 18.2%. Among the 679 patients with HIV-drug-resistance genotyping done before initiating HAART, HIV-drug resistance to any class was observed in 53 (7.8%) of the patients. During follow-up, HIV-drug resistance to any class was observed in 302 (26.5%) participants. Emergence of any resistance was associated with mortality (hazard ratio: 1.75 [95% confidence interval: 1.27, 2.43]). When we considered each class of resistance separately, persons who exhibited resistance to non-nucleoside reverse transcriptase inhibitors had the highest risk: mortality rates were 3.02 times higher (95% confidence interval: 1.99, 4.57) for these patients than for those who did not exhibit this type of resistance. Conclusions We demonstrated that emergence of resistance to non-nucleoside reverse transcriptase inhibitors was associated with a greater risk of subsequent death than was emergence of protease inhibitor resistance. Future research is needed to identify the particular subpopulations of men and women at greatest risk and to elucidate the impact of resistance over a longer follow-up period.

Comparing Objective Measures of Adherence to HIV Antiretroviral Therapy: Electronic Medication Monitors and Unannounced Pill Counts

We compared electronic medication monitoring and electronic monitoring adjusted by interview with an unannounced pill-count adherence measure, in a cross-sectional analysis (n = 42). We used the following measures (a) electronic monitored doses (EMD: # medication monitor openings/# doses prescribed), (b) adjusted electronically monitored doses (AEMD: EMD adjusted by the number of extra openings and extra doses removed), (c) percentage of days dose taken (PDDT: % days the medication monitor was opened at least once, and (d) unannounced pill count (PC). The results showed that AEMD, EMD, and PDDT were significantly associated with PC adherence. AEMD explained 83% of the variation in PC adherence, EMD 49%, and PDDT 58%. EMD adherence was significantly lower than PC adherence (p = .02). Electronic medication monitoring measures were closely related to PC adherence. AEMD was more closely associated than EMD or PDDT. EMD may underestimate adherence due to the removal of multiple doses from the bottle at one time.

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.

Causes of Death on Antiretroviral Therapy: A Post- Mortem Study from South Africa

Background Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients. Methods HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death. Results Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7–90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death. Conclusions Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge.

Is Average Adherence to HIV Antiretroviral Therapy Enough

In this edition of the Journal of General Internal Medicine, Golin et al. report on adherence behavior to antiretroviral therapy in 140 HIV-infected people using electronic medication monitors, pill counts, and patient report.1 The use of multiple adherence measures is an unusual strength of this study and provides important insight regarding our view of normal adherence behavior. Consistent with a small number of other studies using objective measures of adherence,2–7 Golin et al. found that patients receiving combination HIV antiretroviral therapy took 71% of prescribed doses on average. Remarkably, only 6% of patients took 95% of their medications, the minimum level of adherence believed to be necessary for durable viral suppression.3 Does this mean that HIV antiretroviral therapy is doomed because it will lead to incomplete viral suppression, the selection of drug-resistant HIV, and eventual disease progression in the majority of people treated? Golin et al. correctly state that “Nonadherence is widely viewed as a risk factor for drug-resistant virus….” Two frequently cited editorials articulated the early biologic relationship between adherence and antiretroviral drug resistance.8,9 Many investigators, however, interpreted this conceptual framework to mean that nonadherent patients will both fail to derive benefit from therapy and also pose a public health threat vis-a-vis the development and spread of drug-resistant HIV. Although conceptually sound, early data linking nonadherence to the emergence of HIV drug resistance was limited to a few studies with small numbers of patients and/or imprecise measures of adherence.10,11 More recent data suggest that the relationship between resistance and adherence is far more complex than initially assumed, and that resistance to protease inhibitor combination therapy is uncommon at levels of adherence below the 70% average. For example, we found that protease inhibitor resistance was limited to patients with 65% to 100% adherence. Resistance to reverse transcriptase inhibitors was also more common in highly adherent patients.2 Because there were several alternative explanations for this finding, this observation was interpreted cautiously. Further data are accumulating, however, to support the interpretation that protease inhibitor resistance requires above-average levels of adherence. In 2 studies using electronic medication monitors, Walsh et al. found that the number of drug resistance mutations increases linearly with improving adherence in viremic patients,12 and Howard et al. found that resistance was more common in the most adherent patients with detectable viremia.13 Similarly, Gallego et al. found that indinavir resistance was limited to patients reporting >90% adherence.14 During longitudinal observation, we have observed that the rate of accumulating drug resistance mutations increases with improving adherence in viremic patients.15 Taking into consideration higher rates of viral suppression with higher levels of adherence, resistance to non-ritonavir–boosted protease inhibitors may be most common in the 80% to 90% adherence range.16 Although speculative, the lack of drug resistance among patients with below-average adherence may be due to the fact that resistance mutations often reduce replicative capacity (“viral fitness”), and that wild-type virus may be relatively more fit than the replication-impaired, drug-resistant virus in the presence of low drug concentrations. This also suggests that the adherence–resistance relationship may be entirely different for non-nucleoside–based regimens.17 Although incomplete adherence, partial viral suppression, and drug resistance are common, clinical failure (defined as disease progression and/or death) remains uncommon.18–21 Furthermore, high levels of adherence may be associated with both protease inhibitor drug resistance2,13–16 and delayed progression to AIDS and death.22–24 Several factors may contribute to this apparent “disconnect” between virologic failure, drug resistance, and clinical success. First, antiretroviral drug resistance is rarely complete. Most antiviral drugs exert some degree of anti-HIV activity against the drug-resistant variant. Those patients who remain on some therapy despite the presence of drug-resistant virus are likely to derive some treatment benefit. Second, the mutations associated with drug resistance result in virus that replicates less efficiently than wild type, perhaps because drug-associated mutations result in reduced efficiency of the target enzyme.25 This results in a virus that replicates at a lower titer,25 spares thymic function,26,27 and perhaps is less cytopathic.28,29 Finally, reductions in the degree of viral replication or alterations in the inherent pathogenicity of the virus may shift the delicate balance between the host and the virus, resulting in an immune system that is better able to control viral replication immunologically. Selective drug pressure in the setting of high but imperfect levels of adherence suppresses wild-type HIV such that the less-fit drug-resistant variant persists. This is consistent with preliminary observations that CD4 cell increases (a better marker for disease progression than HIV viral load) occur at levels of adherence lower than those required for complete viral suppression.30 While it is both epidemiologically and biologically plausible that patients with incomplete adherence derive durable clinical benefit from therapy, this does not suggest that incomplete adherence is equivalent to perfect adherence. Several studies have demonstrated that adherence is the strongest predictor to progression to AIDS and death after CD4 cell count.22–24 Higher levels of adherence and greater degrees of viral suppression will lead to better outcomes. Theoretically, complete adherence with potent therapy will prevent any viral evolution, thus assuring that drugs will work indefinitely. Thus, complete adherence and viral suppression should remain the goal of therapy. As shown by Golin et al., incomplete adherence, often leading to incomplete viral suppression, is common and should be viewed as normal human behavior rather than a disease in need of a cure. If patients are treated, they will do better. And if they improve their adherence to near perfect levels, they will do even better. Ongoing declines in AIDS-related mortality suggest, however, that average adherence to combination antiretroviral therapy, even if incomplete, is sufficient to profoundly impact the natural history of HIV infection.

Hepatitis C Virus Infection in San Francisco's HIV‐infected Urban Poor

AbstractOBJECTIVE: To measure Hepatitis C Virus (HCV) prevalence, incidence, and initiation of HCV therapy in a representative HIV-infected cohort of the urban poor. DESIGN: Cohort analysis. SETTING: The Research and Access to Care for the Homeless (REACH) Cohort is a systematic sample of HIV-infected marginally housed individuals identified from single-room occupancy hotels, homeless shelters, and free lunch programs in San Francisco. PARTICIPANTS: Two hundred forty-nine participants with 28.9 months (median) of follow-up were studied. Mean age was 44 (range 24 to 75, standard deviation ±8.4) years. Eighty-two percent were male, 43% were African-American, 64% were lifetime injection drug users, and 24% had been on the street or in a shelter in the prior month. INTERVENTIONS: We measured HCV testing and treatment history with structured interviews; additionally, participants were tested for HCV antibodies (EIA-2) with RNA viral load confirmation. MAIN RESULTS: At baseline, 172 (69.1%) were HCV-positive and 182 (73.1%) were HCV-positive at follow-up, including 155 (62.2%) with viremia. HCV-positive status was associated with having injected drugs, elevated serum alanine aminotransferase, homelessness in the last 1 year, and more severe depressive symptoms. The incidence of new HCV infection was 4.63% per person-year (ppy; 95% confidence interval, 2.31 to 8.13) in the entire cohort and 16.77% ppy among injection drug users. The prevalence of HCV antibody-negative HCV-viremia was 13.2% (10/76). Nonwhites were less likely to receive HCV testing and subspecialty referral, controlled for drug use and other confounders. Sixty-eight percent (123/182) were aware treatment was available; however, only 3.8% (7/182) or 1.16% ppy received HCV treatment. CONCLUSIONS: While HCV infection is common, HCV treatment is rare in the HIV-HCV coinfected urban poor. Urban poor, nonwhite individuals are less likely to receive HCV testing and subspecialty referral than their white counterparts. Antibody-negative infection may complicate screening and diagnosis in HIV-infected persons.

Expanding access to HIV antiretroviral therapy among marginalized populations in the developed world

Summary We now have a great deal of evidence demonstratingthat lower income populations, women, ethnic mino-rities, and illicit drug users are at risk of poor access toantiretroviral therapy and higher rates of treatmentdiscontinuation. Although the majority of these studieshave been conducted among living cohorts, data isemerging to suggest that limited access is contributingto the ongoing HIV/AIDS mortality rates in the devel-oped world.Fears regarding the potential for community-widetransmission of antiretroviral resistant HIV amongthe homeless, mentally ill, and injection drug usershave thus far largely been unfounded [58,64,66,100]. Although this concern deserves continuedmonitoring, in many instances it is likely thatresistance is not observed because a proportion ofthese patients will cease antiretroviral therapy out-right or will be insufficiently adherent for resistanceto develop [66].The above issues have several implications. First,interventions to improve retention among those whoinitiate therapy are urgently required, and efforts areneeded to ameliorate barriers to treatment retentionand adherence. Second, among individuals who havenot accessed therapy, strategies to improve contactwith HIV care providers are needed. When contact ismade, guidelines for physicians must be based onavailable evidence [69–71]. This evidence suggeststhat physicians should seek to address modifiablebarriers to adherence and retention in HIV treatmentprior to the start of therapy among patients notrequiring immediate treatment [58,68]. In addition,no patient should be denied the opportunity toinitiate HAART regardless of perceived or realbarriers to optimal adherence including continuedillicit drug use. Given that the extent of the HIV/AIDS public health crisis, and since the full benefitsof HAART are not compromised when patients aresuccessfully retained in treatment, regardless of ethni-city, gender, and history of injection drug use[55,101], efforts to address social, cultural, and medicalbarriers are an urgent priority.