Factors associated with virological response in HIV-infected patients failing antiretroviral therapy: a prospective cohort study

OBJECTIVES: To assess the antiviral response to optimized therapy following genotypic resistance testing and to identify factors associated with virological response in HIV-1-infected patients failing antiretroviral therapy. METHODS: A prospective cohort study was conducted in 344 HIV-1-infected patients who underwent genotypic resistance testing because of virological failure. Virological response was defined as a plasma HIV RNA level below 200 HIV-1 RNA copies/mL or a drop of plasma viral load from baseline of more than 1 log10. A multivariate logistic regression analysis was performed to identify factors associated with virological response. RESULTS: The median age of the patients was 40 years, with a male to female ratio of 4:1. Fifty-one per cent of patients had received the three major classes of antiretrovirals and the median duration of previous antiretroviral therapy was 4.6 years. At baseline, the median plasma HIV RNA level was 4.4 log10 copies/mL and the median CD4 cell count was 274 cells/microL. At 3 months, 55% of patients (188 of 344) had a virological response, which was sustained at 6 months (53%). Predictors of virological response were exposure to two or fewer protease inhibitors [odds ratio (OR) 1.8; P=0.046], and use in optimized therapy of a new class of antiretrovirals (OR 2.9; P=0.006), of more than two new drugs (OR 3.0; P<0.0001), of abacavir (OR 1.9; P=0.03), or of lopinavir/ritonavir (OR 3.7; P=0.0002). CONCLUSIONS: A high proportion of patients achieved a short-term virological response in this cohort study. Patients with the least experience of protease inhibitor treatment and in whom a new class of antiretroviral, more than two new drugs, abacavir or lopinavir/ritonavir was used in optimized therapy had the best virological outcome.     

Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients

OBJECTIVE: To evaluate the effect of drug class-wide resistance (CWR) on survival in HIV-infected individuals who underwent genotypic resistance test after antiretroviral failure. DESIGN: Observational, longitudinal cohort study. METHODS: HIV-infected individuals experiencing treatment failure were enrolled at first genotypic resistance test. End-points were death for any cause, AIDS-related death and AIDS-defining event/death. CWR was defined according to the International AIDS Society consensus. Survival analysis was performed with Cox's model. RESULTS: Among 623 patients enrolled and followed for a median of 19 months (interquartile range, 12-29), Kaplan-Meier analyses for end-points at 48 months in patients with no CWR, one CWR, two CWR or three CWR were 8.9, 11.7, 13.4 and 27.1%, respectively, for death; 6.1, 9.9, 13.4 and 21.5%, respectively, for AIDS-related death; and 16.0, 17.7, 19.3 and 35.9%, respectively, for new AIDS event/death. In a multivariate Cox's model, higher HIV RNA level, previous AIDS and detection of three CWR (hazard ratio, 5.34; 95% confidence interval, 1.76-16.24) were all significantly associated with increased risk of death, while higher CD4 cell count and use of a new boosted protease inhibitor drug after identifying genotypic resistance were associated with reduced risk. Detection of three CWR was also significantly associated with higher risk of AIDS-related death and new AIDS event/death. CONCLUSIONS: Even in the late era of highly effective antiretroviral treatments, detection of CWR, particularly if extended to all three drug classes is related to poorer clinical outcome and represents a risk-marker of disease progression and death.     

Intermittent antiretroviral therapy in patients with controlled HIV infection

BACKGROUND: To assess the safety of a drug-sparing treatment regimen in patients with high CD4 cell counts and controlled HIV replication under antiretroviral therapy. METHODS: An open-label, non-inferiority study involving 403 adults with CD4 cell counts of 450 x 10(6) cells/l or greater and plasma HIV-1-RNA levels less than 200 copies/ml, randomly assigned to switch to an 8-week off, 8-week on regimen or to continue their antiretroviral regimen. The primary endpoint was the proportion of patients reaching a confirmed CD4 cell count less than 300 x 10(6) cells/l. RESULTS: Over 96 weeks, the proportion of patients meeting this endpoint was non-inferior in the intermittent group (3.6 versus 1.5%, upper bound of the 95% confidence interval of the difference 5.6%). No AIDS-defining event and two non-HIV-related deaths (intermittent arm) were recorded. The median decrease from baseline in the CD4 cell count was greater in the intermittent arm (-155 versus -8 x 10(6) cells/l, P < 0.0001). Minor HIV-related events, mainly lymphadenopathy and mucosal candidiasis, were more frequent in the intermittent group (14 versus 7%, P = 0.04) as were thrombocytopenia. The incidence of grade 3-4 non-HIV-related events and laboratory abnormalities were not statistically different between the groups. At week 96, the proportion of patients with plasma HIV-1-RNA levels less than 400 copies/ml were 81 and 90% in the intermittent (8 weeks after treatment resumption) and continuous groups (P = 0.02), respectively, with similar patterns of HIV resistance genotypes. CONCLUSION: Despite some limitations, an 8-week off and on intermittent treatment regimen appeared clinically safe over 96 weeks while sparing half of the drug exposure.     

High levels of adherence do not prevent accumulation of HIV drug resistance mutations

OBJECTIVES: To assess the relationship between development of antiretroviral drug resistance and adherence by measured treatment duration, virologic suppression, and the rate of accumulating new drug resistance mutations at different levels of adherence. METHODS: Adherence was measured with unannounced pill counts performed at the participant's usual place of residence in a prospective cohort of HIV-positive urban poor individuals. Two genotypic resistance tests separated by 6 months (G1 and G2) were obtained in individuals on a stable regimen and with detectable viremia (> 50 copies/ml). The primary resistance outcome was the number of new HIV antiretroviral drug resistance mutations occurring over the 6 months between G1 and G2. RESULTS: High levels of adherence were closely associated with greater time on treatment (P < 0.0001) and viral suppression (P < 0.0001) in 148 individuals. In a subset of 57 patients with a plasma viral load > 50 copies/ml on stable therapy, the accumulation of new drug resistance mutations was positively associated with the duration of prior treatment (P = 0.03) and pill count adherence (P = 0.002). Assuming fully suppressed individuals (< 50 copies/ml) do not develop resistance, it was estimated that 23% of all drug resistance occurs in the top quintile of adherence (92-100%), and over 50% of all drug resistance mutations occur in the top two quintiles of adherence (79-100%). CONCLUSION: Increasing rates of viral suppression at high levels of adherence is balanced by increasing rates of drug resistance among viremic patients. Exceptionally high levels of adherence will not prevent population levels of drug resistance.     

Tenofovir treatment in an unselected cohort of highly antiretroviral experienced HIV positive patients

The aim of the present study was to explore the treatment effect of tenofovir as implemented in clinical practice. Data are presented on 34 patients. 11 patients had tenofovir added to a stable anti-retroviral treatment (ART) and 23 patients had drugs other than tenofovir. CD4 counts, HIV-RNA levels and genotypic resistance were determined at baseline and after 3 and 6 months. After initiation of tenofovir treatment, a mean decrease in HIV-RNA for all 34 patients was observed (-0.43 log1o copies/ml (+/- 1.22) and -0.49 log10 copies/ml (+/- 1.36) after 3 and 6 months, respectively, (p = 0.045)). However, the effect of tenofovir on HIV-RNA in the group of patients who had tenofovir added to a stable ART was limited, and the decrease in HIV-RNA was significantly higher in patients who had drugs other than tenofovir changed as well (p = 0.004 and p = 0.03 after 3 and 6 months, respectively). After initiation of tenofovir treatment, no significant increases in CD4 count were observed. All new NRTI-associated mutations could be explained by the background treatment. In conclusion, we observed a significant decrease in HIV-RNA only when tenofovir was prescribed, in conjunction with other anti-retroviral drugs, to patients on a failing highly active antiretroviral drug regimen (HAART).     

Use of genotypic resistance testing to guide hiv therapy: clinical impact and cost-effectiveness

BACKGROUND: Genotypic sequencing for drug-resistant strains of HIV can guide the choice of antiretroviral therapy. OBJECTIVE: To assess the cost-effectiveness of genotypic resistance testing for patients acquiring drug resistance through failed treatment (secondary resistance) and those infected with resistant virus (primary resistance). DESIGN: Cost-effectiveness analysis with an HIV simulation model incorporating CD4 cell count and HIV RNA level as predictors of disease progression. DATA SOURCES: Published randomized trials and data from the Multicenter AIDS Cohort Study, the national AIDS Cost and Services Utilization Survey, the Red Book, and an institutional cost-accounting system. TARGET POPULATION: HIV-infected patients in the United States with baseline CD4 counts of 0.250 x 10(9) cells/L. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTIONS: Genotypic resistance testing and clinical judgment, compared with clinical judgment alone, in two contexts: after initial treatment failure (secondary resistance testing) and before initiation of antiretroviral therapy (primary resistance testing). OUTCOME MEASURES: Life expectancy, quality-adjusted life expectancy, and cost-effectiveness in dollars per quality-adjusted life-year (QALY) gained. RESULTS OF BASE-CASE ANALYSIS: Secondary resistance testing increased life expectancy by 3 months, at a cost of $17 900 per QALY gained. The cost-effectiveness of primary resistance testing was $22 300 per QALY gained with a 20% prevalence of primary resistance but increased to $69 000 per QALY gained with 4% prevalence. RESULTS OF SENSITIVITY ANALYSIS: The cost-effectiveness ratio for secondary resistance testing remained under $25 000 per QALY gained, even when effectiveness and cost of testing and antiretroviral therapy, quality-of-life weights, and discount rate were varied. CONCLUSIONS: Genotypic antiretroviral resistance testing following antiretroviral failure is cost-effective. Primary resistance testing also seems to be reasonably cost-effective and will become more so as the prevalence of primary resistance increases.     

Predictors of incomplete adherence, virologic failure, and antiviral drug resistance among HIV-infected adults receiving antiretroviral therapy in Tanzania.

BACKGROUND: Access to antiretroviral therapy is rapidly expanding in sub-Saharan Africa. Identifying the predictors of incomplete adherence, virologic failure, and antiviral drug resistance is essential to achieving long-term success. METHODS: A total of 150 subjects who had received antiretroviral therapy for at least 6 months completed a structured questionnaire and adherence assessment, and plasma human immunodeficiency virus (HIV) RNA levels were measured. Virologic failure was defined as an HIV RNA level >400 copies/mL; for patients with an HIV RNA level >1000 copies/mL, genotypic antiviral drug resistance testing was performed. Predictors were analyzed using bivariable and multivariable logistic regression models. RESULTS: A total of 23 (16%) of 150 subjects reported incomplete adherence. Sacrificing health care for other necessities (adjusted odds ratio [AOR], 19.8; P<.01) and the proportion of months receiving self-funded treatment (AOR, 23.5; P=.04) were associated with incomplete adherence. Virologic failure was identified in 48 (32%) of 150 subjects and was associated with incomplete adherence (AOR, 3.6; P=.03) and the proportion of months receiving self-funded antiretroviral therapy (AOR, 13.0; P=.02). Disclosure of HIV infection status to family members or others was protective against virologic failure (AOR, 0.10; P=.04). CONCLUSIONS: Self-funded treatment was associated with incomplete adherence and virologic failure, and disclosure of HIV infection status was protective against virologic failure. Efforts to provide free antiretroviral therapy and to promote social coping may enhance adherence and reduce rates of virologic failure.     

Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study

OBJECTIVE: In a prospective randomized study, the impact of plasma protease inhibitor (PI) trough levels on changes in HIV RNA were assessed in patients treated with genotypic-guided therapy. METHODS: Patients failing combination therapy (HIV-1 RNA > 10,000 copies/ml, and at least 6 months of therapy with nucleoside analogues and 3 months with PI) were randomly assigned into two arms: control group (C) in which the treatment was modified according to the standard of care; genotypic group (G) in which the treatment was modified according to resistance mutation profiles. Serial PI plasma levels were performed in patients throughout the 12 month study. PI levels were determined by high performance liquid chromatography. 'Suboptimal' concentration (SOC) was defined as at least two PI plasma levels below 2 x IC95. Others were defined as 'optimal' concentration (OC). Patients were categorized into four groups: G1 (SOC/control); G2 (OC/control); G3 (SOC/genotype); G4 (OC/genotype). An intent-to-treat analysis was performed with viral load as the primary endpoint. RESULTS: A total of 81 patients [mean age 39.7 +/- 8 years, 59 men, 52.7% Centers for Disease Control and Prevention (CDC) stage C] were included in the pharmacological substudy. The two groups according to randomization arms were comparable in terms of risk factor, age, sex, previous treatments, baseline CD4 cell count, HIV-1 RNA and mean PI plasma concentrations. Linear regression analysis showed a significant relationship between PI concentration and HIV RNA in the plasma. OC and SOC were found in 67.9% (55/81) and 32.1% (26/81) of patients, respectively. Mean changes in HIV RNA from baseline at month 6 were: -0.23 +/- 0.29 log10 copies/ml (G1); -0.97 +/- 0.28 (G2); -0.68 +/- 0.37 (G3); -1.38 +/- 0.20 (G4). Multivariate analysis showed PI plasma concentrations to be an independent predictor of HIV-RNA evolution (P = 0.017). CONCLUSION: Multiple parameters determine the response to antiretroviral therapy and causes other than the development of drug resistance should be considered in the setting of therapeutic failure. Suboptimal concentrations of PI limit the response to antiretroviral therapy. Therapeutic drug monitoring of the PI plasma concentration may therefore prove useful in optimizing antiretroviral therapy.     

Early adoption of HIV-1 resistance testing in the San Diego County Ryan White CARE Act Program: predictors and outcome

This research identifies predictors and outcomes of early use of human immunodeficiency virus type 1 (HIV-1) resistance testing in the San Diego County Ryan White CARE Act program. Between January and November 2000, 98 patients receiving care in 7 clinics participated in the resistance testing program. Provider characteristics predictive of participation included number of patients and percent of practice devoted to HIV care and number of HIV-related continuing medical education hours over the preceding 12 months. Providers rarely requested expert panel review of test results, and expert review was not predictive of better viral load responses. Regimens specified before knowledge of resistance results had more active drugs than those prescribed after knowledge of test results. Phenotypic susceptibility was predictive of virologic response, as was degree of prior nucleoside analogue exposure. There was little relationship between phenotypic susceptibility and a clinician's decision to prescribe a drug. Early adopters of this technology were more experienced HIV providers than their colleagues and utilized susceptibility information using reasoning processes in which resistance was a contributory but not necessarily dominating factor.     

Treatment of HIV-related tuberculosis—unresolved issues

Abstract:   Tuberculosis (TB) is one of the most common opportunistic infections among persons with HIV infection. However, there are uncertainties about both TB and HIV treatment regimens among patients with advanced immunodeficiency. On the TB treatment side, there are lingering concerns about whether patients with advanced immunodeficiency should have a more intensive regimen for TB treatment (longer duration, more frequent [daily] dosing and/or post-treatment isoniazid). The use of antiretroviral therapy among patients with TB and AIDS dramatically decreases the risk of death and other opportunistic infections. However, use of antiretroviral therapy during TB treatment is complicated by the need to coordinate the activities of the TB control program and the HIV care clinic, overlapping side-effect profiles of anti-TB and antiretroviral drugs, drug–drug interactions between the rifamycins and many antiretroviral drugs, and the occurrence of immune reconstitution inflammatory syndrome events. The combination of rifampin-based TB treatment and efavirenz-based antiretroviral therapy is clearly the best option for cotreatment of these two infections. However, there are a number of uncertainties about the optimal antiretroviral therapy if efavirenz cannot be used (because of intolerance, drug resistance, pregnancy or lack of an appropriate formulation in children). The competing risks of AIDS events and severe immune reconstitution inflammatory syndrome events raise uncertainties about the optimal timing of antiretroviral therapy during TB treatment. Despite all of these complexities, the treatment of HIV-related TB can be remarkably successful. I review these unresolved questions in the treatment of HIV-related TB and suggest studies to help resolve them.     

The prevalence of antiretroviral drug resistance in the United States

BACKGROUND: Antiretroviral therapy has dramatically reduced the morbidity and mortality of infection due to HIV. The emergence of drug-resistant virus has limited the usefulness of many drugs. OBJECTIVE: To determine the prevalence of HIV drug resistance in the population of adults receiving care in the United States. DESIGN AND METHODS: HIV drug susceptibility assays were performed on plasma virus from a random sample representative of the 132500 HIV-infected American adults who had received medical care in early 1996 yet were viremic with > 500 copies/ml of HIV RNA in late 1998. A blood sample was obtained from 1797 patients who comprised a representative sample of the 208900 adults receiving urban care for HIV infection in early 1996 who survived to late 1998. The sampling procedure permitted weighting each evaluated patient to reflect demographic and other characteristics of the target population. RESULTS: We estimated that 132500 (63%) of the target population had HIV viremia of > 500 copies/ml. Among viremic patients, an estimated 76% had resistance to one or more antiretroviral drugs. The odds of resistance were significantly higher in patients with a history of antiretroviral drug use, advanced HIV disease, higher plasma HIV viral load and lowest CD4 cell count by self-report. CONCLUSIONS: The frequent selection for drug-resistant virus among viremic patients during the first 3 years of widespread use of potent antiretroviral combination therapy has significant implications for HIV treatment and transmission.     

Adherence, side effects and efficacy of stavudine plus lamivudine plus nelfinavir in treatment-experienced HIV-infected patients

OBJECTIVES: To evaluate adherence, side effects and efficacy of a modality of highly active antiretroviral therapy (HAART) in HIV-infected patients. METHODS: In a cohort, prospective study, 65 previously treated patients received stavudine plus lamivudine plus nelfinavir. Fifty-three participants (81%) had a history of intravenous drug use. Patients were evaluated at 3-month intervals. The association of adherence with demographic variables, hepatitis C virus infection, number of stopped antiretroviral regimens, HIV RNA level, CD4 cell count, and adverse effects to drugs was assessed. RESULTS: After a median follow-up of 12 months, 30 participants (46%) showed adequate adherence in all visits. An association was observed between adherence and female sex: 18 of 47 men (38%) vs. 12 of 18 women (67%) presented adequate adherence in all visits (P=0. 0416). An association was also observed between adherence and low baseline HIV RNA level (P=0.0229). Discontinuation of treatment took place because of refusal to take medication in 11 participants (17%) and because of side effects in seven participants (11%). Undetectable HIV RNA level was achieved in 26 patients (40%) at 3 months and in lower percentages at months 6, 9 and 12. CONCLUSIONS: Overall adherence to the employed HAART regimen was poor. Female sex and low baseline HIV RNA were associated with better adherence. Refusal to take medications and side effects were the main reasons to stop therapy. At 3 months' follow-up, virological efficacy was achieved in 40% of patients.     

Delayed progression to AIDS in volunteers treated with long-term HIV-1 Immunogen (REMUNE) therapy in Thailand

OBJECTIVES: To observe the long-term effects of an immune-based therapy HIV-1 Immunogen (REMUNE; Immune Response Corp., Carlsbad, CA, USA) as a first course of treatment designed to sustain the immune system and thus delay the initiation of therapy with antiretroviral drugs and/or delay disease progression. METHODS: In this open-label, multi-institute extended phase II P2101B study, disease progression, CD4 and CD8 T-cell counts, HIV-1 RNA levels, and genotypic antiretroviral drug resistance were examined in 223 asymptomatic HIV-1-infected Thai volunteers receiving REMUNE every 12 weeks over 132 weeks. A subset of subjects was randomly selected by the physicians to receive antiretroviral drugs for 10 months. RESULTS: Patients treated with REMUNE demonstrated a low rate of clinical disease progression (0.72 per 100 person-years), higher CD4 and CD8 T-cell counts, higher body weight before and after treatment in the same patient, and stable viral load with no serious adverse events. We found no genotypic evidence of drug resistance in subgroups of patients on REMUNE monotherapy or REMUNE plus antiretrovirals (ARTs). CONCLUSIONS: This Thai study, like previous US and European studies, confirms that therapeutic immunization of HIV-infected volunteers modifies disease progression, as evidenced by stabilization of CD4 and CD8 T-cell counts, body weight, and viral load. As the majority of asymptomatic patients demonstrated an objective response to immunization, this study suggests that REMUNE may be utilized prior to initiation of antiviral drug therapy when CD4 cell counts are still above the current ART guidelines. Further work should be carried out to examine its potential use in combination with ART in order to reduce the increasingly common occurrence of drug resistance.     

Adherence to antiretroviral treatments with a protease inhibitor in HIV-infected patients

OBJECTIVE: Long-term therapeutic success of powerful antiretroviral treatments dependent on patient adherence. This study was conducted to assess the difficulties HIV-infected patients with advanced-stage disease encounter in adhering to antiretroviral treatments with a protease inhibitor. PATIENTS AND METHODS: A prospective self-administered questionnaire survey was conducted at our outpatient clinic for 2 months. CD4 counts and HIV viral loads were also determined. RESULTS: Seventy-one percent of the study population which included 262 responded to the questionnaire. The survey was made a median 215 days after initiating the antiprotease treatment with indinavir (71% of the cases), ritonavir (13%), saquinavir (6%), or a combination of protease inhibitors (10%). At onset of antiprotease treatment, mean CD4 count was 171+/-150/mm(3) and mean HIV viral load was 75,000 copies/ml. The treatment was considered to be difficult to take by 43% of the patients; 66% stated they had forgotten to take their drugs at least once a month. It was most difficult to take the drugs prescribed for the afternoon. Shifts of 1 hour were observed in 58% of patients. Non-adherence was frequent (1 failure to take drugs per week), observed in 13% of patients. Most often, the patients stated they had forgotten to take their drugs because of occupational or relational difficulties (52%). Non-adherence increased with duration of treatment. The drug most often associated with non-adherence was indinavir (73%). Age and sex did not influence adherence. Mean RNA HIV serum level was lower than at onset of the antiprotease treatment in the most non-adherent patients. At the time of the questionnaire, there was no difference in serum RNA HIV level or in the percentage of patients with an undetectable level between non-adherent and adherent patients. CONCLUSION: This survey confirmed difficulties in adherence are frequent and worsen with time. No relationship was found between non-adherence and reduction in viral load, suggesting that a short-term effect of these very active drugs despite lack of perfect adherence. Other factors (pharmacology, sensitivity to antiretroviral drugs.) also play a major role in therapeutic success.     

Next-Generation Sequencing to Help Monitor Patients Infected with HIV: Ready for Clinical Use?

Given the extreme variability of the human immunodeficiency virus (HIV) and its ability to replicate as complex viral populations, HIV variants with reduced susceptibility to antiretroviral drugs or with specific coreceptor tropism (CCR5 and/or CXCR4) may be present as minority members of the viral quasispecies. The sensitivity of current HIV genotypic or phenotypic assays is limited, and thus, these tests usually fail to detect low-abundance viral variants. Next-generation (deep) sequencing (NGS) produces an enormous amount of information that allows the detection of minority HIV variants at levels unimaginable using standard Sanger sequencing. NGS technologies continue to evolve, opening new and more affordable opportunities to implement this methodology in clinical laboratories, and HIV is not an exception. The ample use of a battery of more effective antiretroviral drugs, together with careful patient monitoring based on HIV resistance testing, has resulted in HIV-infected patients whose disease is usually well-controlled. The vast majority of adherent patients without detectable resistance become virologically suppressed; however, a subset of these patients with undetectable resistance by standard methods may fail antiretroviral therapy, perhaps due to the presence of minority HIV-resistant variants. Novel NGS-based HIV assays with increased sensitivity for identifying low-level drug resistance and/or coreceptor tropism may play an important role in the success of antiretroviral treatments.     

HIV-1耐药突变的研究进展

至2015年止,全球约有1 700万HIV/AIDS病例得到抗逆转录病毒治疗,使HIV-1死亡率和发病率迅速下降。随着抗逆转录病毒治疗向所有感染HIV者全面推进,HIV耐药突变问题对长期治疗也构成了威胁,并对全球2030年消除艾滋病这一重要公共卫生战略产生了负面影响。本综述试图从不同的经济和地理环境出发,从个体和群体水平上阐述了常用的抗逆转录病毒药物的遗传屏障、交互耐药程度、耐药突变的流行病学和耐药管理;同时本文汇总了高、中低两类国家的可传播性耐药(TDR)和获得性耐药(ADR)的流行方式,分析了两类具有重要的公共卫生意义HIV耐药突变问题,即治疗前耐药和暴露前预防性服药的耐药。此外,鉴于有效地对不同类国家的HIV病例的治疗和管理,分别分析了基因型耐药性检测和治疗实践方面的关联,这些内容对我国的艾滋病防治也具有一定的参考作用。