Determinants of HIV progression and assessment of the optimal time to initiate highly active antiretroviral therapy: PISCIS Cohort (Spain)

OBJECTIVE: We analyze the factors related to progression to AIDS or death in HIV-infected patients from the Proyecto para la Informatización del Seguimiento Clínico epidemiológico de los pacientes con Infección por VIH/SIDA (PISCIS) Cohort and we assess the optimal time to initiate highly active antiretroviral therapy (HAART) taking lead time into account. METHODS: We selected naive patients who were AIDS-free and initiated HAART after January 1998. Statistical analyses were performed using Cox proportional hazards models. Lead time was defined as the time it took the deferred group with an early disease stage to reach the later stage. The analysis accounting for lead time was performed using multiple imputation methods based on estimates from the pre-HAART period as described elsewhere. RESULTS: Multivariate analysis on 2035 patients (median follow-up = 34.3 months) showed significantly higher hazard ratios (HRs) for a CD4 count <200 cells/microL (HR = 3.79, 95% confidence interval [CI]: 2.18 to 6.57), HIV-1 RNA level >100,000 copies/mL (HR = 1.84, 95% CI: 1.26 to 2.69), and hepatitis C virus (HCV) coinfection (HR = 2.40, 95% CI: 1.65 to 3.49), whereas a lower risk was found for those who started HAART between January 2001 and June 2004 (HR = 0.55, 95% CI: 0.30 to 0.90). When lead time and unseen events were included, we found a higher risk of progression to AIDS among patients who deferred treatment when the CD4 count reached <200 cells/microL (HR = 2.97, 95% CI: 1.91 to 4.63) and 200 to 350 cells/microL (HR = 1.85, 95% CI: 1.03 to 3.33) compared with those who started treatment with CD4 counts from 200 to 350 cells/microL and >350 cells/microL, respectively. CONCLUSIONS: Advanced HIV disease, HCV coinfection, and early HAART period were determinants of AIDS progression or death. Lead-time analysis in asymptomatic HIV-infected patients suggests that the best time to start HAART is before the CD4 count falls to lower than 350 cells/microL.     

Is moderate HIV viremia associated with a higher risk of clinical progression in HIV-infected people treated with highly active antiretroviral therapy: evidence from the Italian cohort of antiretroviral-naive patients study

OBJECTIVE: To assess the risk of clinical progression (CP) according to the duration of time spent without complete viral load (VL) suppression compared with that associated with periods of stably suppressed viremia in HIV-infected people who started highly active antiretroviral therapy (HAART) when previously na?ve to antiretrovirals. DESIGN: A cohort study of patients having started HAART after enrollment in the Italian Cohort of Antiretroviral-Naive Patients (ICoNA) and being followed for at least 6 months. METHODS: Person-years spent in different categories according to the VL level and the change in VL from the most recent value before the initiation of HAART were calculated. A multivariable Poisson regression model, including potential confounders, was constructed. RESULTS: A total of 3023 patients were studied. The overall rate of CP was 13.4 per 1000 person-years. Evidence for a higher risk of CP was observed for people with a current VL >10,000 copies/mL. For each year longer spent on HAART with a VL >100,000 copies/mL, a 5-fold increased risk was observed (relative risk [RR] = 5.34, 95% confidence interval [CI]: 2.83 to 1.08; P = 0.0001). An increased risk of CP in patients with current suppression <1.5 log10 copies/mL (RR = 2.34, 95% CI: 1.16 to 4.74; P = 0.02) and in those with no suppression or a VL higher than their set point (RR = 2.39, 95% CI: 1.17 to 4.89; P = 0.02) was observed compared with those with suppression of >3 log10 copies/mL, although it was not significant. Longer duration on HAART with a VL suppressed below set point seemed to confer protection against CP. CONCLUSIONS: Virologic failure to antiretroviral drugs is common. The risk of CP may remain low despite a low but detectable level of HIV viremia.     

Effect of clinical pharmacists on utilization of and clinical response to antiretroviral therapy

OBJECTIVE: To determine the association of clinical pharmacists with health outcomes and utilization measures among HIV-infected patients. METHODS: Observational study of 1571 HIV-infected patients prescribed their initial highly active antiretroviral therapy (HAART) regimen in clinics with and without a clinical pharmacist. Outcomes analyzed were changes in plasma HIV RNA level, CD4 T-cell counts, and service utilization (hospital days, emergency department visits, and office visits) over 24 months based on exposure to a clinical pharmacist. RESULTS: Patients exposed to a clinical pharmacist tended to be more likely to achieve an HIV RNA level <500 copies/mL at 12 months (adjusted odds ratio [OR] = 2.01, 95% confidence interval [CI]: 0.92 to 4.37). At 24 months, however, results depended on the provider panel size; the ORs for panel sizes < or =50 and >50 HIV-infected patients were 1.67 (95% CI: 0.60 to 4.62) and 0.97 (95% CI: 0.39 to 2.41), respectively. CD4 T-cell counts were modestly but nonsignificantly higher for the patients exposed to a clinical pharmacist. Utilization also depended on the provider panel size; pharmacist exposure was associated with 64% (95% CI: 30% to 108%) and 9% (95% CI: -11% to 33%) increases in total hospital days for panel sizes < or =50 and >50 HIV-infected patients, respectively. Pharmacist exposure was also associated with a 19% (95% CI: -13% to -24%) decrease in office visits for panel sizes < or =50 HIV-infected patients, with minimal effect for larger panel sizes. CONCLUSION: Clinical pharmacists seem to contribute to lower office visit rates in antiretroviral-naive patients initiating HAART.     

HIV-associated anal cancer: has highly active antiretroviral therapy reduced the incidence or improved the outcome?

BACKGROUND: Highly active antiretroviral therapy (HAART) has reduced the incidence and improved the survival of patients with Kaposi sarcoma and AIDS-related non-Hodgkin lymphoma. We wished to evaluate its effects on incidence and survival in HIV-associated anal cancer. METHODS: We measured the incidence and survival of patients with invasive anal cancer from our prospective cohort of 8640 HIV-seropositive individuals. RESULTS: In our cohort of 8640 HIV-seropositive individuals, the incidence of invasive anal cancer (diagnosed in 26 patients) is 60 per 100,000 patient-years. This is 120 times higher than in the age- and gender-matched general population. The incidence of invasive anal cancer in the HIV cohort was 35 (95% confidence interval CI: 15-72) per 100,000 patient-years of follow-up in the pre-HAARTera (1984-1995) and 92 (95% CI: 52-149) per 100,000 patient-years of follow-up in the post-HAARTera (1996-2003) (P > 0.05). These figures are significantly higher than those for the general population (P < 0.001 for both) and give a relative risk of 67 and 176 in the pre- and post-HAART eras, respectively, compared with the general population. The 5-year overall survival is 47% (95% CI: 24%-70%), and the 5-year disease-free survival is 66% (95% CI: 45%-87%). There is no difference in overall survival between the pre- and post-HAART eras (log rank P = 0.19). CONCLUSIONS: Unlike other HIV-associated cancers, there has been no significant change in the incidence, clinical features, or overall survival since the introduction of HAART.     

Outcome of a second-line protease inhibitor-containing regimen in patients failing or intolerant of a first highly active antiretroviral therapy

The outcome of second-line protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART) was investigated in 263 patients who were failed by (n = 148) or intolerant of (n = 115) a first HAART regimen. The endpoints were virologic failure (decline in HIV RNA < 1 log10 copies/ml after > or = 2 months) and discontinuation due to intolerance/toxicity. During a median follow-up of 483 days (33-1087 days), 154 patients (59%) discontinued the second regimen, 86 (33%) because of intolerance/toxicity; another 135 patients (51.3%) showed virologic failure. Independent factors associated with virologic failure (Cox's model) were 7 to 12 months of first HAART (hazard ratio [HR] 1.70 versus < or = 6 months: 95% confidence interval [CI], 1.08-2.70) and gender (HR 1.58 males versus females: 95% CI, 1.04-2.30); the negatively associated factors were advanced age (HR 0.61 > 34 years versus < or = 34 years: 95% CI, 0.42-0.88), a saquinavir-containing first HAART (HR 0.57 versus indinavir: 95% CI, 0.34-0.93) and change due to intolerance/toxicity (HR 0.58 versus failure: 95% CI, 0.35-0.98). The independent variables predictive of discontinuation due to intolerance/toxicity were the reason for switching (HR 1.79 intolerance versus failure: 95% CI, 1.02-3.16) and the first protease inhibitor (PI) regimen (HR 0.42 ritonavir versus indinavir: 95% CI, 0.22-0.80). Given that patients who are failed by a first regimen are at high risk of having rescue therapy fail as well, second-line regimens including therapies directed by testing of drug resistance patterns of clinical viral isolates are warranted. Patients experiencing toxicity due to a first PI-containing regimen are at risk of toxicity to other PIs and should be addressed to PI-sparing HAART.     

Structured treatment interruptions in primary HIV-1 infection: the ANRS 100 PRIMSTOP trial

BACKGROUND: Whether structured treatment interruptions (STIs) can induce anti-HIV immune response and control HIV replication following discontinuation of highly active antiretroviral therapy (HAART) in patients with primary HIV infection is controversial. METHODS: In this multicenter, prospective trial, patients with early symptomatic primary HIV infection were given HAART continuously for 34 weeks. Afterward, patients with plasma viral load (PVL) <50 copies/mL entered the STI phase, which consisted of 3 consecutive periods of 2, 4, and 8 weeks off HAART, each separated by 12 weeks on HAART. HAART was permanently stopped at week 84 and patients were followed up for 24 weeks. The primary endpoint for definition of virologic success was a PVL <50 copies/mL during the 6 months following HAART discontinuation. RESULTS: Of the 29 patients enrolled, 26 completed the trial. Six months after HAART discontinuation, only 1 patient (3.8%, 95% CI: 0.1% to 19.6%) had PVL <50 copies/mL, whereas 6 of 26 (23.1%, 95% CI: 9.0% to 43.7%) had PVL <1000 copies/mL. Female gender was the only parameter significantly associated with a PVL <1000 copies/mL. No other parameter, either at baseline or before HAART discontinuation, predicted virologic success at week 108. A major protease inhibitor resistance mutation (L90M) developed in 3 patients. CONCLUSIONS: This trial failed to confirm that a significant proportion of patients with primary HIV infection can maintain suppression of viremia after a sequence of HAART/STIs followed by HAART discontinuation.     

Effects of depression and selective serotonin reuptake inhibitor use on adherence to highly active antiretroviral therapy and on clinical outcomes in HIV-infected patients

OBJECTIVES: To determine the impact of depression on highly active antiretroviral therapy (HAART) adherence and clinical measures and investigate if selective serotonin reuptake inhibitors (SSRIs) improve these measures. DESIGN: Retrospective cohort study. METHODS: In 2 large health maintenance organizations, we measured the effects of depression (with and without SSRI use) on adherence and changes in viral and immunologic control among HIV-infected patients starting a new HAART regimen. HAART adherence, HIV RNA levels, and changes in CD4 T-cell counts through 12 months were measured. RESULTS: A total of 3359 patients were evaluated; 42% had a depression diagnosis, and 15% used SSRIs during HAART. Depression without SSRI use was associated with significantly decreased odds of achieving > or =90% adherence to HAART (odds ratio [OR] = 0.81, 95% confidence interval [CI]: 0.70 to 0.98; P = 0.03). Depression was associated with significantly lower odds of an HIV RNA level <500 copies/mL (OR = 0.77, 95% CI: 0.62 to 0.95; P = 0.02). Depressed patients compliant with SSRI medication (>80% adherence to SSRI) had HAART adherence and viral control statistically similar to nondepressed HIV-infected patients taking HAART. Comparing depressed with nondepressed HIV-infected patients, CD4 T-cell responses were statistically similar; among depressed patients, those compliant with SSRI had statistically greater increases in CD4 cell responses. CONCLUSIONS: Depression significantly worsens HAART adherence and HIV viral control. Compliant SSRI use is associated with improved HIV adherence and laboratory parameters.     

Use of viral load measured after 4 weeks of highly active antiretroviral therapy to predict virologic outcome at 24 weeks for HIV-1-positive individuals

Early prediction of suboptimal viral response to highly active antiretroviral therapy (HAART) is vital to prevent early development of drug resistance. We used logistic regression to predict the odds of achieving virologic suppression (<50 copies/mL) after 24 weeks of HAART in 656 antiretroviral-naive patients starting HAART at the J.W. Goethe University, Chelsea and Westminster, and Royal Free Hospitals according to their week 4 viral load. Therapy changes involving the switch of a single antiretroviral were assumed to have occurred for toxicity reasons and ignored. Because complete regimen changes or additions of new antiretrovirals could be due to virologic failure, patients were counted as virological failures at week 24. Three hundred sixty (84%) of 430 patients with viral loads of <1000 copies/mL, 106 (61%) of 175 with viral loads between 1001 and 10,000 copies/mL, 11 (37%) of 30 with viral loads between 10,001 and 100,000 copies/mL, and 5 (24%) of 21 with viral loads of >100,000 copies/mL at week 4 subsequently attained virologic suppression at 24 weeks. The odds of attaining virologic suppression at 24 weeks was 65% lower for every 1-log higher viral load at week 4 (odds ratio, 0.35; 95% confidence interval, 0.27-0.45). The proportion of patients with an undetectable viral load at 24 weeks among those who have not attained a viral load of <1000 copies/mL by 4 weeks is quite low. We suggest that this group of patients should be particularly closely monitored.     

Predictors of antiretroviral treatment failure in an urban HIV clinic

BACKGROUND: Predictors of antiretroviral treatment (ART) failure are not well characterized for heterogeneous clinic populations. METHODS: A retrospective analysis was conducted of HIV-infected patients followed in an urban HIV clinic with an HIV RNA measurement < or =400 copies/mL on ART between January 1, 2003, and December 31, 2004. The primary endpoint was treatment failure, defined as virologic failure (> or =1 HIV RNA measurement >400 copies/mL), unsanctioned stopping of ART, or loss to follow-up. Prior ART adherence and other baseline patient characteristics, determined at the time of the first suppressed HIV RNA load on or after January 1, 2003, were extracted from the electronic health record (EHR). Predictors of failure were assessed using proportional hazards modeling. RESULTS: Of 829 patients in the clinic, 614 had at least 1 HIV RNA measurement < or =400 copies/mL during the study period. Of these, 167 (27.2%) experienced treatment failure. Baseline characteristics associated with treatment failure in the multivariate model were: poor adherence (hazard ratio [HR] = 3.44; 95% confidence interval [CI]: 2.34 to 5.05), absolute neutrophil count <1000/mm (HR = 2.90, 95% CI: 1.26 to 6.69), not suppressed on January 1, 2003 (HR = 2.69, 95% CI: 1.78 to 4.07) or <12 months of suppression (HR = 1.64, 95% CI: 1.10 to 2.45), CD4 count <200 cells/mm (HR = 1.90, 95% CI: 1.31 to 2.76), nucleoside-only regimen (HR = 1.75, 95% CI: 1.08 to 2.82), prior virologic failure (HR = 1.70, 95% CI: 1.22 to 2.39) and > or =1 missed visit in the prior year (HR = 1.56, 95% CI: 1.13 to 2.16). CONCLUSIONS: More than one quarter of patients in a heterogeneous clinic population had treatment failure over a 2-year period. Prior ART adherence and other EHR data readily identify patient characteristics that could trigger specific interventions to improve ART outcomes.     

Effectiveness and safety of abacavir, lamivudine, and zidovudine in antiretroviral therapy-naive HIV-infected patients: results from a large multicenter observational cohort

OBJECTIVE: To analyze the safety and effectiveness of abacavir, lamivudine, and zidovudine (ABC/3TC/ZDV) in antiretroviral therapy (ART)-naive HIV-infected patients. DESIGN: Retrospective observational cohort study. METHODS: We analyzed all consecutive ART-naive HIV-infected patients who initiated ABC/3TC/ZDV in 71 centers throughout Spain and had a clinical visit and laboratory data at least 16 weeks after initiating this regimen. We assessed safety, mortality, new AIDS-defining conditions (ADCs) and treatment failure, the latter defined by any of the following: (1) reduction in plasma HIV-1 viral load (pVL) <1 log during the first 12 weeks of ART, unless it was less than the lower limit of quantification (LOQ); (2) failure to achieve a pVL or = LOQ after achieving a pVL 相似文献   

Why are baseline HIV RNA levels 100,000 copies/mL or greater associated with mortality after the initiation of antiretroviral therapy?

BACKGROUND: There is conflicting evidence regarding the impact of baseline plasma HIV RNA on virologic responses after the initiation of triple-drug antiretroviral therapy (highly active antiretroviral therapy [HAART]). This has made it difficult to interpret the recently reported association between baseline plasma HIV RNA and mortality. We evaluated whether baseline CD4 cell count and plasma HIV RNA predicted virologic suppression (<500 copies/mL) and rebound (> or =500 copies/mL) among adherent HIV-infected patients. METHODS: Antiretroviral-naive HIV-infected patients were stratified by baseline CD4 cell count, plasma HIV RNA, and adherence level. Cox and logistic regression were used to evaluate the time to suppression and rebound and the odds of ever achieving HIV RNA suppression. RESULTS: A total of 1422 individuals initiated HAART between August 1, 1996 and July 31, 2000 and were followed to March 31, 2002. Adherent patients with HIV RNA levels > or =100,000 copies/mL and 50 to 99,999 copies/mL were slower to suppress HIV RNA than patients with baseline HIV RNA <50,000 copies/mL in Kaplan-Meier analyses. Although the odds of RNA suppression among adherent patients with baseline RNA levels <50,000 copies/mL and 50 to 99,999 copies/mL were similar (P = 0.197), patients with baseline HIV RNA > or =100,000 copies/mL were markedly less likely ever to achieve suppression during follow-up (adjusted odds ratio: 0.27 [95% confidence interval: 0.13-0.54]; P < 0.001). No differences in the rate of virologic rebound were observed between adherent patients in the various baseline HIV RNA strata, and CD4 cell count was not associated with suppression or rebound. CONCLUSIONS: Baseline HIV RNA > or =100,000 copies/mL was associated with a significantly lower likelihood of ever achieving HIV RNA suppression during follow-up. These findings likely explain the association between baseline HIV RNA levels and mortality and have important implications for the development of therapeutic guidelines.     

Primary HIV drug resistance and efficacy of first-line antiretroviral therapy guided by resistance testing

BACKGROUND: Primary HIV drug resistance has been associated with poor treatment outcome of first-line highly active antiretroviral therapy (HAART) in several trials. The aim of the study was to assess the efficacy of first-line HAART guided by resistance testing. METHODS: In a prospective multicenter study in the state of Nordrhein-Westfalen, Germany, chronically HIV-infected patients underwent genotypic resistance testing and were monitored for 48 weeks after initiation of HAART. RESULTS: Primary drug resistance was found in 30 of 269 patients entering the study between January 2001 and December 2003 [11.2%; 95% confidence interval, 7.4-14.9]. In intent-to-treat analysis, the proportion of patients with viral load below 50 copies/mL after 24 and 48 weeks was 70.0% and 66.7%, respectively, in patients with resistance and 74.1% and 73.6%, respectively, in patients without (P = 0.66 and 0.51). In on-treatment analysis, the proportions were 80.8% and 83.3%, respectively, in patients with resistance and 81.9% and 85.0%, respectively, in patients without (P= 0.79 and 0.77). These results were also valid considering a detection limit of 400 copies/mL. CONCLUSIONS: The prevalence of primary drug resistance was 11.2% in chronically HIV-infected patients. HAART guided by resistance testing had similar efficacy in patients with primary drug resistance as compared with patients with wild-type virus. Based on these facts, resistance-adapted first-line HAART is suggested as routine practice.     

Incidence of and risk factors for symptomatic visceral leishmaniasis among human immunodeficiency virus type 1-infected patients from Spain in the era of highly active antiretroviral therapy

The way in which the extensive use of highly active antiretroviral therapy (HAART) has influenced the incidence of visceral leishmaniasis (VL) among human immunodeficiency type 1 (HIV-1)-infected patients is not yet understood. The present study assessed whether the incidence of symptomatic VL in HIV-infected patients has decreased since the introduction of HAART. Likewise, the role of other potential risk factors for VL was also analyzed. Therefore, 479 HIV-1-infected patients receiving antiretroviral treatment, according to the available drugs at each moment, were prospectively followed from April 1989 to June 2000 in two university hospitals in southern Spain. A bone marrow aspiration was performed when patients showed symptoms suggestive of kala-azar. A diagnosis of VL was made when Leishmania amastigotes were seen in Giemsa-stained samples or promastigotes were cultured in specific media. The median follow-up time was 1,380 [8 to 4,536] days. Twenty-one patients were diagnosed with symptomatic VL. The density of incidence of VL has decreased 64.8% as of January 1997, when HAART began to be used extensively in our area. The use of HAART was the main independent factor associated with VL; this therapy was a protective factor (adjusted hazard ratio [HR], 0.05; 95% confidence interval [CI], 0.02 to 0.15). CDC clinical category C at entry in the cohort (HR, 4.08; 95% CI, 1.46 to 11.35) and CD4(+) cell counts below 300 cells/mm(3) during the follow-up (HR, 3.96; 95% CI, 1.56 to 10.01) were also independently associated with kala-azar. A VL diagnosis prior to follow-up and low compliance with antiretroviral therapy were not independently associated with symptomatic VL, although statistical significance was almost reached (P = 0.1 and P = 0.08, respectively). In summary, the use of HAART has led to a fall in the incidence of symptomatic VL in HIV-infected patients. The main risk factor associated with kala-azar emergence in patients infected with HIV is deep immunosuppression.     

Gender differences in virologic response to treatment in an HIV-positive population: a cohort study

OBJECTIVE: To establish whether a gender difference in virologic response to highly active antiretroviral treatment (HAART) exists. METHODS: A cohort of HIV-positive individuals was examined. OUTCOMES: Achievement of viral load <500 copies/ml and "failure" (failure to suppress viral load <500 copies/ml after 24 weeks or two consecutive measurements above this level after having suppressed below it). Hazard ratios (HRs) comparing the rate in women to that in men were derived using the Cox model. RESULTS: Of 366 male subjects, 79% were white and 82% were homosexual. Sixty-three percent of the 91 female subjects were African and 87% were heterosexual. The median follow-up after HAART was 94 weeks. The baseline CD4 count was higher in men (228 x 106 per liter) than in women (171 x 106 per liter) (p =.01), but the viral load was similar (p =.88). The median time to <500 copies/ml was 16 weeks. Women achieved a viral load of <500 copies/ml at a faster rate than men, with an adjusted HR of 1.46 (95% confidence interval [CI]: 0.99-2.16; p =.06). Some 261 patients failed treatment (58% of men and 53% of women) with an HR of 0.78 (95% CI: 0.51-1.21; p =.27). CONCLUSIONS: Women may achieve virologic suppression at a faster rate than men and have a more durable response. Further research should examine these responses in conjunction with clinical outcomes, because gender differences in virologic response may ultimately be of little relevance if clinical outcomes are similar.     

Relationship Between Low Bone Mineral Density and Highly Active Antiretroviral Therapy Including Protease Inhibitors in HIV-Infected Patients

Abstract

Purpose: The objectives of this study were to determine the prevalence of osteopenia and the factors associated with its presence in HIV-infected patients under highly active antiretroviral therapy (HAART) and to assess the changes of bone mineral density (BMD) in a population followed prospectively. Method: BMD was assessed by dual-energy X-ray absorptiometry (DEXA) scans at the lumbar spine and at the femoral neck in 78 HIV-infected patients who had previously received HAART as the first antiretroviral regimen and in 11 antiretroviral-naive HIV-infected patients. BMD measurements were repeated in 70 treated patients who had completed 1 year of follow-up. Results: Thirty-seven (42%) patients showed osteopenia at any localization. The prevalence of osteopenia in PI-naive patients was 23% versus 49% in individuals who had received PI at any moment [p = .001; adjusted odds ratio (95% CI) = 0.11 (0.02-0.48)]. The frequency of osteopenia was significantly higher among men than among women [50% vs. 17%; p = .016; adjusted OR (95% CI) = 12.1 (2.22-66.20)]. The level of plasma albumin was independently associated with osteopenia [adjusted OR (95% CI) per each g/dL of plasma albumin decrease 2.55 (1.18-10)]. In patients in whom a second DEXA was done, no significant changes in BMD were found. Conclusion: The prevalence of osteopenia in HIV-infected patients on HAART is high. Loss of BMD is associated with PI therapy, low plasma albumin level, and male sex. Osteopenia does not progress after 1 year of continued HAART.     

Interruption of highly active antiretroviral therapy in HIV clinical practice: results from the Italian Cohort of Antiretroviral-Naive Patients

OBJECTIVES: To investigate the frequency of a first therapy interruption (TI) > or = 12 weeks, to identify the factors associated with TI and with therapy resumption, and to compare the risk of developing clinical events during TI and during continuous therapy. METHODS: Observational study of 3142 patients who started a first highly active antiretroviral therapy (HAART) regimen. End points were time to (1) first TI of > or = 12 weeks, (2) subsequent therapy resumption, and (3) development of new AIDS-related events or death. RESULTS: Over a median follow-up period of 41 months (interquartile range: 18-60 months), 721 patients (22.9%) interrupted HAART for > or = 12 weeks, with a probability of 28.6% (95% confidence interval [CI]: 26.7-30.6) by 4 years from the date of therapy initiation. Patient decision (47.4%) and toxicity (24.0%) were the main reasons for TI. Women, injection drug users, and patients with a higher current CD4 cell count were more likely to interrupt. The median time to therapy resumption was 12 months (95% CI: 11-14). The higher the current CD4 count, the slower was the rate of resuming therapy; conversely, patients who stopped because of failure and those with a pre-HAART viral load >100,000 copies/mL resumed therapy sooner. Two hundred eighty-one patients experienced clinical progression at a rate of 2.6 per 100 person-years (pys) (95% CI: 2.3-3.0) while patients were on therapy and 3.5 per 100 pys (95% CI: 2.4-4.8) during TI. The adjusted relative hazard of clinical progression associated with TI was 2.75 (95% CI: 1.14-6.65; P = 0.03). CONCLUSIONS: TI occurring in clinical practice is associated with an increased risk of clinical progression; hence, it should be discouraged outside strictly experimental settings.     

Differences in HIV disease progression by injecting drug use in HIV-infected persons in care

BACKGROUND: In the United States and many Western countries, injecting drug use continues to be an important cause of HIV infection. This has important clinical and public health implications if injecting drug users (IDUs) have greater barriers to antiretroviral effectiveness than other risk groups. We assessed if there were differences between HIV-infected IDUs and non-IDU patients in the development of AIDS-defining illnesses (ADIs) from the time the patients started their first combination antiretroviral therapy (CART) regimen. METHODS: We compared clinical outcomes for IDU patients (n = 827) with those for non-IDU patients (n = 1314) after they started CART. We controlled for financial access, because all patients had access to CART through insurance or a drug assistance program. The incidence (number of ADI cases per 100 person-years) was compared for IDUs and non-IDUs from 1995 through 2002. Incidence ratios were calculated for IDUs compared with non-IDUs. Risk factors for development of ADIs were assessed using negative binomial regression. RESULTS: From 1995-1996 to 2001-2002, there was a decline in ADI incidence among IDUs from 31.9 to 16.2 cases per 100 person-years of follow-up. Over the same time, there was a decline in ADI incidence among non-IDUs from 37.0 to 9.7 cases per 100 person-years. The incidence ratio (incidence among IDUs compared with that among non-IDUs) increased from 0.87 (95% confidence interval [CI], 0.65-1.15) to 1.67 (95% CI, 1.25-2.18) from 1995-1996 to 2001-2002. By negative binomial regression, the incidence ratio for ADIs among IDUs versus non-IDUs increased to 1.45 (95% CI, 1.21-1.75), after 1998, adjusting for differences in demographic, clinical, and treatment factors. CONCLUSIONS: The relative incidence of ADIs among IDUs with access to treatment increased approximately 50% compared with non-IDUs since 1999. This suggests greater barriers to the effective use of CART for IDUs, resulting in a higher individual and public health burden of clinical HIV disease. It will be important to understand reasons for this growing difference and to implement appropriate interventions to improve the effective use of CART for IDUs.     

Psychiatric illness and virologic response in patients initiating highly active antiretroviral therapy

BACKGROUND: Mental illness (MI) and substance abuse (SA) are common in HIV-positive patients. MI/SA consistently predict poorer antiretroviral adherence, suggesting that affected patients should be at higher risk of poor virologic and immunologic response to highly active antiretroviral therapy (HAART). PARTICIPANTS: 198 HAART-naive patients initiated HAART at an academic medical center serving a heterogeneous population. METHODS: Participants were assigned a predicted probability from 0 to 1 of having each of the following: (1) any mood, anxiety, or substance use disorder; (2) clinically relevant depression; (3) alcohol abuse/dependence; and (4) drug abuse/dependence. Probabilities were based on responses to questions on an MI/SA screening instrument (Substance Abuse and Mental Illness Symptoms Screener [SAMISS]) and other clinical and sociodemographic characteristics and were derived using predictive logistic regression modeling from a separate validation study of the SAMISS compared with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnoses. Using survival analysis techniques, we assessed baseline predicted probability of psychiatric illness as a predictor of time from HAART initiation to virologic suppression (first viral load [VL] <400 copies/mL), from HAART initiation to overall virologic failure (first VL >or=400 copies/mL after suppression, time set to 0 for patients never achieving suppression), from virologic suppression to virologic rebound (first VL >or=400 copies/mL), and from HAART initiation to immunologic failure (first CD4 cell count lower than baseline). RESULTS: A higher predicted probability of any psychiatric disorder was associated with a slower rate of virologic suppression (adjusted hazard ratio [aHR] = 0.86 per 25% increment, 95% confidence interval [CI]: 0.75 to 0.98) and a faster rate of overall virologic failure (aHR = 1.22, 95% CI: 1.06 to 1.40). Associations with other outcomes were consistent in direction but not statistically significant. Predicted probability of depression was associated with slower virologic suppression (aHR = 0.79, 95% CI: 0.63 to 0.98), and predicted probabilities of alcohol and drug abuse/dependence was associated with faster overall virologic failure (aHR = 1.37, 95% CI: 1.08 to 1.74 and aHR = 1.18, 95% CI: 1.00 to 1.39, respectively). CONCLUSIONS: These results are consistent with an inferior virologic response to first HAART among patients with concurrent mood, anxiety, and substance use disorders, suggesting a clinical benefit to identification and treatment of psychiatric illness among patients initiating antiretroviral therapy.     

Mortality during the first 24 months after delivery in relation to CD4 T-lymphocyte levels and viral load in a cohort of breast-feeding HIV-1-infected women in Dar es Salaam, Tanzania

The objective of this study was to analyze the mortality during the first 24 months after delivery in relation to CD4 T-lymphocyte levels and viral load at enrollment (36 weeks of gestation) in a cohort of HIV-1-seropositive breast-feeding women at the Dar es Salaam site of the multicenter Petra trial (a mother-to-child HIV-1 transmission intervention trial using antiretroviral therapy). Antiretroviral treatment was not available in this setting apart from the short treatment given within the trial around delivery to prevent mother-to-child transmission of HIV. T-lymphocyte subsets were determined by flow cytometry. Plasma HIV-1 RNA was quantified by the Amplicor HIV-1 RNA Monitor v 1.5 assay. Mortality after delivery was analyzed using the life-table technique and Cox regression. The analysis included 266 mothers. The CD4 cell counts at enrollment were <200 cells/mm in 14.5% of the mothers. The viral load at enrollment was >100,000 RNA copies/mL in 33.6% of the mothers. The mortality 24 months after delivery was 6.7% (95% CI = 3.1-10.1%). The mortality 24 months after delivery was 29.9% (95% CI = 13.1-46.9%) for mothers with <200 CD4 cells/mm at enrollment, 3.3% (95% CI = 0-6.6%) for mothers with 200-499 CD4 cells/mm, 2.9% (95% CI = 0-7.1%) for mothers with >500 CD4 cells/mm (P = 0.0000), 15.0% (95% CI = 6.6-23.4%) for mothers with viral load >100,000 copies/mL at enrollment, and 2.8% (95% CI = 0-5.6%) for mothers with viral load <100,000 copies/mL (P = 0.0000). In the multivariate analysis CD4 cell counts and viral load were both independent risk factors for mortality (P < 0.001 and P = 0.004, respectively). In conclusion, the mortality was high among women with severe immunosuppression or high viral load at enrollment, but not in the rest of the women. CD4 lymphocyte count in late pregnancy was a better predictor of death within 2 years than was viral load. The results support the World Health Organization recommendation to initiate antiretroviral treatment in resource-limited settings in HIV-1-infected adults with CD4 cell counts <200/mm and show that this is appropriate also among perinatal women.     

Gender differences in HIV-1 RNA rebound attributed to incomplete antiretroviral adherence among HIV-Infected patients in a population-based cohort

BACKGROUND: There have been growing concerns about possible gender-related differences in rates of responses to highly active antiretroviral therapy (HAART). We therefore examined the association between gender and time to HIV-1 RNA rebound in antiretroviral-naive HIV-infected patients initiating HAART in a population-based setting. METHODS: We evaluated all antiretroviral-naive HIV-infected men and women who achieved HIV-1 RNA suppression at least once (HIV RNA <500 copies/mL) after initiating HAART between August 1, 1996 and July 31, 2000 and who were followed until March 31, 2002 in a province-wide HIV treatment program. We evaluated time to HIV-1 RNA rebound (> or =500 copies/mL) using Kaplan-Meier methods and Cox proportional hazards regression. RESULTS: In total, 844 (87.0%) men and 126 (13.0%) women initiated HAART during the study period and achieved HIV-1 RNA suppression at least once. Overall rates of rebound were 47.4% and 34.0% for women and men, respectively (log-rank, P < 0.021). Women were less likely to be > or =95% adherent (P = 0.001) and more likely to have a history of injection drug use (P = 0.001). In multivariate analysis, incomplete adherence was found to be highly predictive of HIV-1 RNA rebound (adjusted relative hazard [ARH] = 4.00, 95% confidence interval [CI]: 3.33-5.00). Although female patients had higher rates of HIV-1 RNA rebound in univariate analysis (relative hazard [RH] = 1.39, 95% CI: 1.05-1.82), this was no longer statistically significant once other known confounders such as adherence and injection drug use were adjusted for (RH = 0.95, 95% CI: 0.71-1.28). When the analyses were stratified based on history of injection drug use, we found that rates of rebound were higher among injection drug-using women than among injection drug-using men (P = 0.048), whereas there was no gender difference among non-injection drug users with respect to rebound (P = 0.345). CONCLUSIONS: We found that higher rates of HIV-1 RNA rebound among women were primarily explained by incomplete adherence, which was more prevalent among women in this cohort. Our findings suggest that psychosocial factors such as drug use and incomplete adherence predict HIV-1 RNA rebound and that gender differences in time to rebound can be largely attributed to a disproportionate prevalence of these factors among women in this population.