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.     

Second-Line Antiretroviral Therapy: Long-Term Outcomes in South Africa

BACKGROUND:: Currently, boosted protease inhibitor-containing regimens are the only option after first-line regimen failure available for patients in most resource-limited settings, yet little is known about long-term adherence and outcomes. METHODS:: We enrolled patients with virologic failure (VF) who initiated lopinavir/ritonavir-containing second-line antiretroviral therapy (ART). Medication possession ratios were calculated using pharmacy refill dates. Factors associated with 12-month second-line virologic suppression [viral load (VL) <50 copies/mL] and adherence were determined. RESULTS:: One hundred six patients (median CD4 count and VL at failure: 153 cells/mm and 28,548 copies/mL, respectively) were enrolled. Adherence improved after second-line ART switch (median adherence 6 months prior, 67%; median adherence during initial 6 months of second-line ART, 100%; P = 0.001). Higher levels of adherence during second-line ART was associated with virologic suppression at month 12 of ART (odds ratio 2.5 per 10% adherence increase, 95% CI 1.3 to 4.8, P = 0.01). Time to virologic suppression was most rapid among patients with 91%-100% adherence compared with patients with 80%-90% and <80% adherence (log rank test, P = 0.01). VF during 24 months of second-line ART was moderate (month 12: 25%, n = 32/126; month 18: 21%, n = 23/112; and month 24: 25%, n = 25/99). CONCLUSIONS:: The switch to second-line ART in South Africa was associated with an improvement in adherence, however, a moderate ongoing rate of VF-among approximately 25% of patients receiving second-line ART patients at each follow-up interval-was a cause for concern. Adherence level was associated with second-line ART virologic outcome, helping explain why some patients achieved virologic suppression after switch and others did not.     

The influence of psychosocial characteristics and race/ethnicity on the use, duration, and success of antiretroviral therapy

BACKGROUND: Expanded access to antiretroviral therapy (ART) has produced dramatic reductions in HIV-associated morbidity and mortality. Disparities in access to and benefit from ART have been observed by race, gender, and mental health status, however. METHODS: From 2001 to 2002, 611 HIV-positive patients were consecutively recruited from 5 southeastern US states and followed for 3 years. We evaluated demographic and psychosocial predictors of probability of receiving ART among all those eligible for ART (on ART, CD4 <350 cells/mm3 or viral load [VL] >55,000 copies/mL in the year preceding enrollment), time to first ART discontinuation among those on ART, and time to VL >400 copies/mL among those on ART with VL <400 copies/mL at enrollment. RESULTS: Of 611 participants, 474 consented to medical record abstraction and had known ART status at enrollment; 81% (385 of 474) of all participants and 89% (385 of 435) of ART-eligible participants were receiving ART at enrollment. In multivariable analyses, ART receipt was associated with greater age (adjusted odds ratio = 1.92 per 10 years, 95% confidence interval: 1.23 to 3.01), fewer recent stressful life events (odds ratio = 0.68, 95% confidence interval: 0.51 to 0.92), less alcohol use (odds ratio = 0.64, 95% confidence interval: 0.46 to 0.90), and greater perceived self-efficacy (OR = 2.82, 95% confidence interval: 1.41 to 5.62). No psychosocial characteristics were associated with ART discontinuation or virologic failure. No racial/ethnic or gender disparities were observed in ART receipt; however, minority racial/ethnic groups were faster to discontinue ART (adjusted hazard ratio = 2.44, 95% confidence interval: 1.33 to 4.49) and experience virologic failure (adjusted hazard ratio = 2.01, 95% confidence interval: 1.09 to 3.71). CONCLUSIONS: Patients with unfavorable psychosocial profiles were less likely to be on ART, perhaps attributable to providers' or patients' expectations of readiness. Psychosocial characteristics were not associated with ART discontinuation or virologic failure, however, possibly reflecting the selection process involved in who initiates ART. Racial disparities in ART discontinuation and virologic failure merit further attention.     

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.     

Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study)

OBJECTIVE: This study evaluated maintenance with lopinavir/ritonavir monotherapy vs. continuing lopinavir/ritonavir and 2 nucleosides in HIV-infected patients with suppressed HIV replication. DESIGN: Randomized, controlled, open-label, multicenter, pilot clinical trial. METHODS: Adult patients were eligible if they had no history of virologic failure while receiving a protease inhibitor, were receiving 2 nucleosides + lopinavir/ritonavir (400/100 mg b.i.d.) for >1 month and had maintained serum HIV RNA <50 copies/mL for >6 months prior to enrollment. RESULTS: Forty-two patients were randomly assigned 1:1 to continue or stop the nucleosides. At baseline there were no significant differences between groups in median CD4 cells/muL (baseline or nadir), pre-HAART (highly active antiretroviral therapy) HIV log10 viremia, or time with HIV RNA <50 copies/mL prior to enrollment. After 48 weeks of follow-up, percentage of patients remaining at <50 HIV RNA copies/mL (intention to treat, M = F) was 81% for the monotherapy group (95% CI: 64% to 98%) vs. 95% for the triple-therapy group (95% CI: 86% to 100%); P = 0.34. Patients in whom monotherapy failed had significantly worse adherence than patients who remained virally suppressed on monotherapy. Monotherapy failures did not show primary resistance mutations in the protease gene and were successfully reinduced with prerandomization nucleosides. Mean change in CD4 cells/microL: +70 (monotherapy) and +8 (triple) (P = 0.27). Mean serum fasting lipids remained stable in both groups. No serious adverse events were observed. CONCLUSION: Most of the patients maintained with lopinavir/ritonavir monotherapy remain with undetectable viral load after 48 weeks. Failures of lopinavir/ritonavir monotherapy were not associated with the development of primary resistance mutations in the protease gene and could be successfully reinduced adding back prior nucleosides.     

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.     

Ecological Study of the Predictors of Successful Management of Dyslipidemia in HIV-Infected Patients on ART: the Swiss HIV Cohort Study

Abstract

Purpose: Antiretroviral therapy (ART) may induce metabolic changes and increase the risk of coronary heart disease (CHD). Based on a health care system approach, we investigated predictors for normalization of dyslipidemia in HIV–infected individuals receiving ART. Method: Individuals included in the study were registered in the Swiss HIV Cohort Study (SHCS), had dyslipidemia but were not on lipidlowering medication, were on potent ART for ≥3 months, and had ≥2 follow-up visits. Dyslipidemia was defined as two consecutive total cholesterol (TC) values above recommended levels. Predictors of achieving treatment goals for TC were assessed using Cox models. Results: Analysis included 958 individuals with median followup of 2.3 years (IQR 1.2–4.0). 454 patients (47.4%) achieved TC treatment goals. In adjusted analyses, variables significantly associated with a lower hazard of reaching TC treatment goals were as follows: older age (compared to 18–37 year olds: hazard ratio [HR] 0.62for 45–52 year olds, 95% CI 0.47–0.82; HR 0.40 for 53–85, 95% CI 0.29–0.54), diabetes (HR 0.39, 95% CI 0.26–0.59), history of coronary heart disease (HR 0.27, 95% CI 0.10–0.71), higher baseline TC (HR 0.78, 95% CI 0.71–0.85), baseline triple nucleoside regimen (HR0.12 compared to PI–only regimen, 95% CI 0.07–0.21), longer time on PI–only regimen (HR 0.39, 95% CI 0.33–0.46), longer time on NNRTI only regimen (HR 0.35, 95% CI 0.29–0.43), and longer time on PI/NNRTI regimen (HR 0.34, 95% CI 0.26–0.43). Switching ART regimen when viral load was undetectable was associated with a higher hazard of reaching TC treatment goals (HR 1.48, 95% CI 1.14–1.91). Conclusion: In SHCS participants on ART, several ART–related and not ART-related epidemiological factors were associated with insufficient control of dyslipidemia. Control of dyslipidemia in ART recipients must be further improved.     

Long-term virological outcome in children receiving first-line antiretroviral therapy

Background

Studies relating to long-term virological outcomes among children on first-line antiretroviral therapy (ART) from low and middle-income countries are limited.

Methods

Perinatally HIV infected, ART-naive children, between 2 and 12 years of age, initiating NNRTI-based ART during 2010–2015, with at least 12 months of follow-up, were included in the analysis. CD4 cell counts and plasma HIV-1 RNA were measured every 24 weeks post-ART initiation. Immunologic failure was defined as a decrease in the CD4 count to pre-therapy levels or below and virologic failure as HIV-RNA of >?1000 copies/ml at 48 weeks after ART initiation. Genotypic resistance testing was performed for children with virologic failure. Logistic regression analysis was done to identify predictors of virologic failure.

Results

Three hundred and ninety-three ART-naïve children living with HIV [mean (SD) age: 7.6 (3) years; mean (SD) CD4%: 16% (8); median (IQR) HIV-RNA: 5.1 (3.5–5.7) log₁₀ copies/ml] were enrolled into the study. At 48 weeks, significant improvement occurred in weight-for-age and height-for-age z-scores from baseline (all p?<?0.001). The immunologic response was good; almost 90% of children showing an increase in their absolute CD4⁺ T cell count to more than 350 cells/mm³. Immunological failure was noted among 11% (28/261) and virologic failure in 29% (94/328) of children. Of the 94 children with virologic failure at 12 months, 36 children showed immunologic failure while the rest had good immunologic improvement. There was no demonstrable correlation between virologic and immunologic failure. 62% had reported >?90% adherence to ART. At the time of virologic failure, multiple NNRTI-associated mutations were observed: 80%—K103N and Y181C being the major NNRTI mutations—observed. Sensitivity (95% CI) of immunologic failure to detect virologic failure was 7% (2–12), specificity 97% (92.4–98.9), PPV 44% (13.7–78.8) and NPV was 72% (65–77.9). There were no statistically significant predictors to detect children who will develop virologic failure on treatment.

Conclusions

Considerable immunological improvement is seen in children with ART initiation, but may not be an effective tool to monitor treatment response in the long-term. There is a lack of correlation between immunologic and virologic response while on ART, which may lead to a delay in identifying treatment failures. Periodic viral load monitoring is, therefore, a priority.

     

Discordant immunologic and virologic responses to highly active antiretroviral therapy are associated with increased mortality and poor adherence to therapy

OBJECTIVE: To examine the independent association of discordant virologic and immunologic responses to highly active antiretroviral therapy (HAART) with mortality. METHODS: A population-based study of 1527 treatment-naive individuals initiating HAART used Cox proportional hazards modeling to determine the independent association of treatment response at 3 to 9 months with nonaccidental mortality. Logistic regression was used to examine associations with discordant responses. RESULTS: Viral load (VL)/CD4 discordant responses were seen in 235 (15.4%) of subjects, and VL/CD4 responses were seen in 179 (11.7%) of subjects. In adjusted Cox regression models, discordant responses were found to be independently associated with an increased risk of mortality (VL/CD4: relative hazard [RH] = 1.87, 95% confidence interval [CI]: 1.15 to 3.04; VL/CD4: RH = 2.47, 95% CI: 1.54 to 3.95). VL/CD4 discordance was found to be associated with increasing age, baseline HIV RNA load <100,000 copies/mL, baseline CD4 counts <50 cells/muL, the use of lamivudine (3TC)/zidovudine (ZDV), and poor adherence to therapy. VL/CD4 discordance was associated with younger age; injection drug use; baseline HIV RNA load >100,000 copies/mL; the use of 3TC/ZDV, didanosine (ddI)/3TC, or ddI/stavudine; and poor adherence to therapy. CONCLUSION: Discordant responses are independently associated with an increased risk of mortality and are, in turn, associated with poor adherence to therapy.     

Plasma HIV-1 RNA decline within the first two weeks of treatment is comparable for nevirapine, efavirenz, or both drugs combined and is not predictive of long-term virologic efficacy: A 2NN substudy

BACKGROUND: The initial rate of plasma HIV-1 RNA (pVL) decline has been proposed as a marker of early efficacy of antiretroviral therapy (ART) and a possible predictor of late efficacy. We compared the rate of pVL decline in patients starting ART with nevirapine (NVP), efavirenz (EFV), or both drugs combined in addition to lamivudine (3TC) and stavudine (d4T). METHODS: Analysis of the viral decay constant (VDc) during the first 2 weeks of treatment in patients enrolled in the 2NN study who remained on allocated treatment. RESULTS: The median VDc (log10 copies per day, [interquartile range]) was similar for NVP (0.30 [0.25-0.36], EFV (0.31 [0.27-0.37]), and NVP + EFV (0.30 [0.27-0.36]). Patients with a baseline pVL >100,000 copies/mL were 8.7 (95% confidence interval [CI]: 6.2-12.3) times more likely to have a VDc >75th percentile. A high VDc was not associated with plasma drug concentration or with a decreased risk of virologic failure at week 48 after the start of therapy (hazard ratio = 0.8, 95% CI: 0.6-1.2). CONCLUSION: NVP, EFV, or NVP + EFV in combination with 3TC and d4T show similar rates of pVL decline during the first 2 weeks of treatment. The VDc with these regimens is not predictive of late virologic efficacy.     

Use of and adherence to antiretroviral therapy is associated with decreased sexual risk behavior in HIV clinic patients

Previous research suggested that the availability of highly active antiretroviral therapy (ART) was associated with increased risky sexual behavior. This study examined the relationship between unprotected anal or vaginal sex (UAV) and ART use and adherence in a cross-sectional survey conducted in 874 randomly selected, sexually active patients at 6 public HIV clinics in California. Patients completed a standardized interview in 1998-1999 regarding HIV history, sexual behavior, illicit drug use, and ART use and adherence. Thirty-four percent reported UAV, defined as anal or vaginal sex without a condom within the past 3 months. Of 79% on ART, 26% reported <95% adherence. Decreased odds for UAV were found for both ART use, odds ratio (OR) 0.5 (95% CI 0.4-0.7, P < 0.001) and adherence to ART of > or = 95%, OR 0.6 (95% CI 0.4-0.8, P < 0.001). These relationships persisted in most stratified analysis for both ART use and adherence but in multivariate analysis only for ART use. An undetectable HIV RNA was associated with decreased odds of UAV, OR 0.6 (95% CI 0.5-0.8, P < 0.001). Contrary to expectations, use of and adherence to ART and their consequent suppression of HIV were associated with a decreased prevalence of self-reported risky sexual behavior.     

Effectiveness of first-line antiretroviral therapy in the IPEC cohort,Rio de Janeiro,Brazil

Background

While Brazil has had a long-standing policy of free access to antiretroviral therapy (ART) for all in need, the epidemiological impact of ART on human immunodeficiency virus (HIV) RNA suppression in this middle-income country has not been well evaluated. We estimate first-line ART effectiveness in a large Brazilian cohort and examine the socio-demographic, behavioral, clinical and structural factors associated with virologic suppression.

Methods

Virologic suppression on first-line ART at 6, 12, and 24 months from start of ART was defined as having a viral load measurement ≤400 copies/mL without drug class modification and/or discontinuation. Drug class modification and/or discontinuation were defined based on the class of a particular drug. Quasi-Poisson regression was used to quantify the association of factors with virologic suppression.

Results

From January 2000 through June 2010, 1311 patients started first-line ART; 987 (75%) patients used NNRTI-based regimens. Virologic suppression was achieved by 77%, 76% and 68% of patients at 6, 12 and 24 months, respectively. Factors associated with virologic suppression at 12 months were: >8 years of formal education (compared to <4 years, risk ratio (RR) 1.13, 95% confidence interval (95% CI) 1.03-1.24), starting ART in 2005-2010 (compared to 2000-2004, RR 1.25 95% CI 1.15-1.35), and clinical trial participation (compared to no participation, RR 1.08 95% CI 1.01-1.16). Also at 12 months, women showed less virologic suppression compared to heterosexual men (RR 0.90 95% CI 0.82-0.99). For the 24-month endpoint, in addition to higher education, starting ART in the later period, and clinical trial participation, older age and an NNRTI-based regimen were also independently associated with virologic suppression.

Conclusions

Our results show that in Brazil, a middle-income country with free access to treatment, over three-quarters of patients receiving routine care reached virologic suppression on first-line ART by the end of the first year. Higher education, more recent ART initiation and clinical trial participation were associated with improved outcomes both for the 12-month and the 24-month endpoints, suggesting that further studies are needed to understand what aspects relating to these factors lead to higher virologic suppression.

     

Clinical, biologic, and behavioral predictors of early immunologic and virologic response in HIV-infected patients initiating protease inhibitors

Predictors of virologic (plasma HIV RNA viral load [VL] < 500 copies/ml) and immunologic (rise in CD4+ cell count > 50 cells/mm3) response after 4 months of therapy (M4) were studied in 750 HIV-1-infected patients prospectively enrolled at the initiation of a protease inhibitor (PI)-containing regimen. A virologic response was observed in 80% of patients, and an immunologic response was observed in 64%. Sixty-two percent of patients self-reported full adherence to therapy at 1 month of therapy (M1) and M4. In multivariate analysis, a virologic response was more frequent in fully adherent patients (odds ratio [OR] = 2.0; p =.001). An immunologic response was associated with age < 36 years (OR =1.4; p =.03), baseline VL (OR = 1.5 per 1 log10 copies/ml higher; p <.01), decrease in VL at M1 (OR = 1.5 per 1 log10 copies/ml decrease; p <.01), baseline total lymphocyte count (OR = 1.7 per 50% lower; p <.001), and baseline CD4+ cell percentage > or = 20% (OR =1.9; p <.001) but not with adherence to therapy. Full adherence seems to be a major predictor of a virologic response to PI-containing triple therapy. An immunologic response may be possible despite incomplete adherence, at least early in therapy.     

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