Subsequent Virologic Rebound Research Articles

Socioeconomic status and treatment outcomes for individuals with HIV on antiretroviral treatment in the UK: cross-sectional and longitudinal analyses

SummaryBackgroundFew studies have assessed the effect of socioeconomic status on HIV treatment outcomes in settings with universal access to health care. Here we aimed to investigate the association of socioeconomic factors with antiretroviral therapy (ART) non-adherence, virological non-suppression, and virological rebound, in HIV-positive people on ART in the UK.MethodsWe used data from the Antiretrovirals, Sexual Transmission Risk and Attitudes (ASTRA) questionnaire study, which recruited participants aged 18 years or older with HIV from eight HIV outpatient clinics in the UK between Feb 1, 2011, and Dec 31, 2012. Participants self-completed a confidential questionnaire on sociodemographic, health, and lifestyle issues. In participants on ART, we assessed associations of financial hardship, employment, housing, and education with: self-reported ART non-adherence at the time of the questionnaire; virological non-suppression (viral load >50 copies per mL) at the time of questionnaire in those who started ART at least 6 months ago (cross-sectional analysis); and subsequent virological rebound (viral load >200 copies per mL) in those with initial viral load of 50 copies per mL or lower (longitudinal analysis).FindingsOf the 3258 people who completed the questionnaire, 2771 (85%) reported being on ART at the time of the questionnaire, and 2704 with complete data were included. 873 (32%) of 2704 participants reported non-adherence to ART and 219 (9%) of 2405 had virological non-suppression in cross-sectional analysis. Each of the four measures of lower socioeconomic status was strongly associated with non-adherence to ART, and with virological non-suppression (prevalence ratios [PR] adjusted for gender/sexual orientation, age, and ethnic origin: greatest financial hardship vs none 2·4, 95% CI 1·6–3·4; non-employment 2·0, 1·5–2·6; unstable housing vs homeowner 3·0, 1·9–4·6; non-university education 1·6, 1·2–2·2). 139 (8%) of 1740 individuals had subsequent virological rebound (rate=3·6/100 person-years). Low socioeconomic status was predictive of longitudinal rebound risk (adjusted hazard ratio [HR] for greatest financial hardship vs none 2·3, 95% CI 1·4–3·9; non-employment 3·0, 2·1–4·2; unstable housing vs homeowner 3·3, 1·8–6·1; non-university education 1·6, 1·1–2·3).InterpretationSocioeconomic disadvantage was strongly associated with poorer HIV treatment outcomes in this setting with universal health care. Adherence interventions and increased social support for those most at risk should be considered.FundingNational Institute for Health Research.

Full Viral Suppression, Low-Level Viremia, and Quantifiable Plasma HIV-RNA at the End of Pregnancy in HIV-Infected Women on Antiretroviral Treatment.

There is limited information on full viral suppression and low-level HIV-RNA viremia in HIV-infected women at the end of pregnancy. We investigated HIV-RNA levels close to delivery in women on antiretroviral treatment in order to define rates of complete suppression, low-level viremia, and quantifiable HIV-RNA, exploring as potential determinants some clinical and viroimmunological variables. Plasma samples from a national study in Italy, collected between 2003 and 2012, were used. According to plasma HIV-RNA levels, three groups were defined: full suppression (target not detected), low-level viremia (target detected but <37 copies/ml), and quantifiable HIV-RNA (≥37 copies/ml). Multivariable logistic regression was used to define determinants of full viral suppression and of quantifiable HIV-RNA. Among 107 women evaluated at a median gestational age of 35 weeks, 90 (84.1%) had HIV-RNA <37 copies/ml. Most of them (59/90, 65.6%) had full suppression, with the remaining (31/90, 34.4%) showing low-level viremia (median: 11.9 copies/ml; IQR 7.4-16.3). Among the 17 women with quantifiable viral load, median HIV-RNA was 109 copies/ml (IQR 46-251), with only one case showing resistance (mutation M184V; rate: 9.1%). In multivariable analyses, women with higher baseline HIV-RNA levels and with hepatitis C virus (HCV) coinfection were significantly more likely to have quantifiable HIV-RNA in late pregnancy. Full viral suppression was significantly more likely with nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens and significantly less likely with higher HIV-RNA in early pregnancy. No cases of HIV transmission occurred. In conclusion, HIV-infected pregnant women showed a high rate of viral suppression and a low resistance rate before delivery. In most cases no target HIV-RNA was detected in plasma, suggesting a low risk of subsequent virological rebound and development of resistance. Women with high levels of HIV-RNA in early pregnancy and those who have concomitant HCV infection should be considered at higher risk of having quantifiable HIV-RNA at the end of pregnancy.

The importance of viral blips and duration of therapy initiated in primary infection in maintaining viral control after stopping cART.

IntroductionAfter achieving undetectable HIV-RNA on cART, on cessation, HIV-RNA rebounds to pre-treatment values for the majority due to the presence of an inaccessible viral reservoir. There is some evidence that cART during primary HIV infection (PHI) limits the reservoir size, optimizing the chance of maintaining viral control off cART. Data are required to predict possible viral controllers for treatment interruption following cART. This analysis aims to investigate the effect of cART duration and the rate of viral blips while on cART initiated in PHI, and other factors on maintaining viral control for those stopping cART.Material and MethodsUsing CASCADE data on HIV seroconverters, we characterized virologic blip (viral suppression on cART followed by a single HIV-RNA above a blip threshold and a subsequent measure below the threshold without cART change) rates for those starting cART within six months of seroconversion (SC). Using Cox models, we examined the effect of the following factors on time to virologic rebound (HIV-RNA>1000) after cART stop: cART duration, severity/rate of blips on cART, time from SC to cART start, cART class, SC year, SC age, CD4 at cART start/stop, sex and HIV risk group.ResultsThe 660 individuals initiating cART in PHI were mostly male (91%), seroconverting between 1995 and 2012, with a median (IQR) age of 34 (29, 41) years mostly infected through sex between men (73%). Median cART duration was 14.8 (7.0, 31.7) months initiated at a median 1.9 (0.5, 3.9) months post SC. 13 (11, 16), 9 (7, 11), 6 (5, 9) and 7 (6, 10)% of individuals experienced blips >50, 100, 200 and 400 copies/mL, respectively. Of those who experienced blips, most (77–90%, depending on blip threshold) experienced just one. Among 250 individuals with undetectable HIV-RNA at cART stop, median time to rebound was 1.6 (0.30, 5.8) months. Time on cART was the only factor independently associated with control after stopping, HR for rebound=0.91 (0.86, 0.98) per extra six months spent on cART, HR for ever blipping >400 copies/mL while on cART=0.88 (0.40, 1.93).ConclusionsBlips occur in about 10% of individuals who initiate cART in PHI, most of who experience only one blip, but was not predictive of subsequent virologic rebound. Increasing time spent on cART initiated in PHI could increase time of virological suppression after cART stop.

Quantification of Viral Loads Lower than 50 Copies per Milliliter by Use of the Cobas AmpliPrep/Cobas TaqMan HIV-1 Test, Version 2.0, Can Predict the Likelihood of Subsequent Virological Rebound to &gt;50 Copies per Milliliter

After 1 year of follow-up, patients on HAART with a baseline viral load (VL) of <20 copies/ml showed significantly lower odds of virological rebound to two consecutive VLs of >50 copies/ml than those with baseline VLs of 20 to 39 and 40 to 49 (P < 0.001). The time to virological rebound was also significantly shorter (P < 0.001) for the groups with baseline VLs of 20 to 39 and 40 to 49.

Clinical Implications of the Nelfinavir‐Proton Pump Inhibitor Drug Interaction in Patients with Human Immunodeficiency Virus

To determine if the concomitant use of nelfinavir and proton pump inhibitors (PPIs) in patients with human immunodeficiency virus (HIV) infection results in the loss of virologic control. Retrospective cohort study. Pharmacy, laboratory, and administrative databases of a large integrated health care system in northern California. A total of 1147 HIV-positive adults who started nelfinavir therapy between November 1, 1998, and June 20, 2003; within this cohort, 141 patients (12.3%) were also prescribed PPIs. The effects on two virologic outcomes--achievement of undetectable HIV viral load and subsequent virologic rebound--were compared between patients receiving nelfinavir alone and those receiving nelfinavir with PPIs. Cox proportional hazards models were used, with adjustments for age, sex, race, HIV risk factors, hepatitis B or C coinfection, and other concurrent drugs known to affect the metabolism of nelfinavir. The use of PPIs had little effect on the ability to achieve an undetectable HIV viral load (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.58-1.19, p=0.29), but there was an approximate 50% increased risk of virologic rebound with the concurrent use of PPIs (adjusted HR 1.53, 95% CI 1.06-2.19, p=0.02). Short-term use of PPIs (defined as within 30 days of initial PPI dispensation) was not associated with increased risk of virologic rebound (HR 1.07, 95% CI 0.26-4.41, p=0.93) compared with no use of PPIs. Use of PPIs should be minimized or avoided in patients who have attained an undetectable HIV viral load while taking a nelfinavir-based antiretroviral regimen. However, concomitant use of these drugs may be acceptable for indications where PPIs are required for fewer than 30 days.

Physical and Psychological Symptoms and Risk of Virologic Rebound Among Patients With Virologic Suppression on Antiretroviral Therapy

We examined the association of self-reported physical and psychological symptoms with subsequent virologic rebound among patients with viral suppression on combination antiretroviral therapy (cART). We included 188 HIV patients from a routine London clinic, who completed a questionnaire on heath/treatment issues in 2005, and were on cART, with viral load (VL) < 50 c/mL. Symptom measures were based on the Memorial Symptom Assessment Scale Short Form, and additional questions: (1) physical symptom score; (2) psychological symptom score; (3) global symptom score; (4) total number of symptoms; (5) anxiety/depression; and (6) suicidal thoughts. Associations with time to (1) VL > 200 c/mL and (2) VL > 50 c/mL were assessed, considering each symptom measure separately. Of 188 patients, 22 experienced VL > 200 c/mL and 46 experienced VL > 50 c/mL (median follow-up: 2.2 years). Risk of VL > 200 c/mL was increased 4- to 5-fold for the highest versus lowest tertiles for the symptom scores (measures 1-3) and total number of symptoms (measure 4), and almost 4-fold for anxiety/depression (measure 5). Associations remained after adjustment for demographic and treatment-related factors (P = 0.006 to P = 0.050, measures 1-5), and were little attenuated after additional adjustment for subject-reported nonadherence (P = 0.011 to P = 0.072). There was a weaker, nonsignificant association with suicidal thoughts (measure 6). For risk of VL > 50 c/mL, all symptom measures were positively associated with rebound risk (P = 0.019 to P = 0.053, measures 1-6, adjusted for demographic and treatment-related factors; P = 0.022 to P = 0.084 after additional adjustment for nonadherence). Among patients on successful cART, physical and psychological symptoms were strongly predictive of viral rebound. Simple symptom inquiry may be valuable in the clinical setting to identify patients at risk of treatment failure, and provide opportunity for intervention.

Not All Missed Doses Are the Same: Sustained NNRTI Treatment Interruptions Predict HIV Rebound at Low-to-Moderate Adherence Levels

BackgroundWhile the relationship between average adherence to HIV potent antiretroviral therapy is well defined, the relationship between patterns of adherence within adherence strata has not been investigated. We examined medication event monitoring system (MEMS) defined adherence patterns and their relation to subsequent virologic rebound.Methods and ResultsWe selected subjects with at least 3-months of previous virologic suppression on a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen from two prospective cohorts in France and North America. We assessed the risk of virologic rebound, defined as HIV RNA of >400 copies/mL according to several MEMS adherence measurements.Seventy two subjects were studied, five of them experienced virologic rebound. Subjects with and without virologic rebound had similar baseline characteristics including treatment durations, regimen (efavirenz vs nevirapine), and dosing schedule. Each 10% increase in average adherence decreased the risk of virologic rebound (OR = 0.56; 95% confidence interval (CI) [0.37, 0.81], P<0.002). Each additional consecutive day off therapy for the longest treatment interruption (OR = 1.34; 95%CI [1.15, 1.68], P<0.0001) and each additional treatment interruption for more than 2 days (OR = 1.38; 95%CI [1.13, 1.77], P<0.002) increased the risk of virologic rebound. In those with low-to-moderate adherence (i.e. <80%), treatment interruption duration (16.2 days versus 6.1 days in the control group, P<0.02), but not average adherence (53.1% vs 55.9%, respectively, P = 0.65) was significantly associated with virologic rebound.ConclusionsSustained treatment interruption may pose a greater risk of virologic rebound on NNRTI therapy than the same number of interspersed missed doses at low-to-moderate adherence.

Cellular HIV-1 DNA load predicts HIV-RNA rebound and the outcome of highly active antiretroviral therapy

To assess whether cellular HIV-1 DNA prior to highly active antiretroviral therapy (HAART) initiation predicts its outcome. Patients included all 51 hemophiliacs of the Greek component of the Multicenter Hemophilia Cohort Study who had initiated HAART and for whom cryopreserved lymphocyte samples before HAART initiation were available. Cellular HIV-1 DNA quantification was performed by a molecular beacon-based real-time PCR assay in multiple samples per patient with a median (interquartile range) follow-up of 76 (45-102) weeks. The median (range) baseline HIV-1 DNA load was 297 (< 10 to 3468) copies per 1 x 10(6) peripheral blood mononuclear cells. Baseline HIV-1 DNA load did not predict initial virological response (VR). None of the patients with initial VR and baseline HIV-1 DNA load at or below the median experienced a subsequent virological rebound, while the cumulative probability of virological rebound by week 104 was 55% among those with HIV-1 DNA load greater than the median (P < 0.008). Cellular HIV-1 DNA load was the only parameter associated with sustained virological response as shown by univariate or multivariate analyses [adjusted odds ratio (95% confidence interval) 0.197 (0.048-0.801) per 1 log10 increase in DNA copies, P = 0.023]. Low cellular HIV-1 DNA load is a marker of sustained virological response in patients with initial VR and it can reliably predict the long-term success of HAART.

Comparison of Virologic, Immunologic, and Clinical Response to Five Different Initial Protease Inhibitor-Containing and Nevirapine-Containing Regimens

Context: The effectiveness of different protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors outside the setting of clinical trials has not been well described. Objectives: To compare five different PI- and nevirapine (NVP)-containing regimens on virologic, immunologic, and clinical outcomes and treatment discontinuation. Design and Setting: Observational cohort study based on an HIV clinic in London. Patients: A total of 690 patients who received either saquinavir hard gel (SQV HG) (n = 183), indinavir (IDV) (n = 189), nelfinavir (NFV) (n = 109), ritonavir (RTV) (n = 42), ritonavir with saquinavir hard gel (RTV/SQV HG) (n = 45), or NVP (n = 122) as part of an initial PI- or NVP-containing treatment regimen between November 1994 and December 1998. A total of 351 (51%) patients had prior exposure to nucleoside reverse transcriptase inhibitors (NRTIs). Main Outcome Measures: The main outcome measures were virologic undetectability, subsequent virologic rebound, CD4 cell count rise, development of AIDS, and treatment discontinuation. All analyses were stratified for year of initiation of the PIor NVP-containing regimen. Results: Overall, 63% of patients attained an undetectable viral load (VL) within 6 months of starting their PI or NVP regimen. The adjusted relative hazard (95% confidence interval [CI]) for an undetectable VL relative to SQV HG was (in rank order): 2.77 (CI: 1.84-4.17) for NFV, 2.54 (CI: 1.81-3.57) for IDV, 2.43 (CI: 1.52-3.87) for RTV, 2.08 (CI: 1.28-3.37) for RTV/SQV HG, and 1.96 (CI: 1.35-2.85) for NVP. Forty-nine percent of patients experienced VL rebound within 12 months of initial attainment of undetectability, but relative to SQV HG, this did not differ significantly across the different PI and NVP regimens. The CD4 cell count response and rate of AIDS events were also similar across the different regimens. No independent predictors of VL undetectability were identified, but prior NRTI exposure was associated with VL rebound, and a lower baseline VL and CD4 cell count were associated with a reduced CD4 count response. The frequency (95% CI) of treatment discontinuation differed across the regimens; at 6 months, it was lowest for NFV (18% [CI: 13%-24%]), IDV (25% [CI: 22%-29%]), and NVP (28% [CI: 22%-34%]) and highest for RTV (41% [CI: 31%-52%]) and SQV HG (52% [CI: 48%-57%]). Conclusions: Although PI- and NVP-containing regimens were similar in their CD4 cell count response and rates of subsequent VL rebound, differences were observed in time to VL undetectability and discontinuation rates relative to SQV HG. SQV HG was consistently inferior to the other PIs and NVP. The use of NFV and IDV was associated with the highest rates of undetectability, and together with NVP, the lowest rates of discontinuation.

Durable HIV Treatment Benefit Despite Low-Level Viremia

LEFT UNTREATED, HUMAN IMMUNODEFICIENCY VIRUS (HIV) replicates at a rapid rate, with the eventual production of billions of new virus particles per day. Given the propensity of HIV to mutate, the possibility exists that each newly produced virus contains at least 1 new mutation. Thus, from a darwinian perspective, ongoing viral replication in the presence of therapy should result in the rapid selection of drug resistance mutations and subsequent virologic rebound. These basic principles have provided the theoretical context for the “hit hard” therapeutic approach to HIV disease. According to current treatment guidelines, complete viral suppression should be the goal of therapy. Once therapy is initiated, plasma viremia, as measured by the concentration of viral RNA in plasma, should decrease to below the level of detection using the most sensitive assay available. Persistent viremia suggests ongoing viral replication and treatment failure. The findings from 2 articles in this issue of THE JOURNAL raise questions about this conceptual framework, and based on data from the 2 studies, it may be argued that “complete” viral suppression may not be a prerequisite for durable treatment benefit. Hermankova and colleagues present studies involving patients who had achieved and maintained an undetectable plasma HIV RNA level ( 50 copies/mL). Using sensitive techniques to amplify plasma viral RNA, virus was identified in plasma in 10 of 20 patients. Genotypic analysis of the isolated viral RNA revealed no evidence of new drugassociated mutations clearly related to the current regimen. The findings indicate that viral replication (defined by the release of virus into plasma) can be identified in patients apparently responding to combination therapy, but that this level of replication appears to be insufficient to select for drug resistance. Havlir and colleagues addressed a similar question in a completely different manner. Patients enrolled in a longterm treatment study were identified retrospectively and stratified into 2 groups: those whose plasma HIV RNA levels remained consistently below the level of detection ( 50 copies/mL) and those whose plasma HIV RNA levels were transiently detectable ( 50 copies/mL of RNA with a subsequent measured level of 50 copies/mL) and who were categorized as having intermittent viremia. Despite evidence of higher levels of viral replication in the latter group (although not uniformly statistically significant), both groups had similar rates of virologic failure. The occurrence of 2 consecutive HIV RNA levels greater than 200 copies/mL was considered virologic failure. Before discussing the implications of these data, it is critical to assess whether the presence of HIV RNA in plasma signifies ongoing viral replication. Hermankova and colleagues suggest low-level viremia may simply reflect the release of archived virus from long-lived cellular reservoirs into plasma and not necessarily continuous rounds of productive infection. The hypothesis that viral replication is ongoing in patients with low-level viremia is supported by several independent lines of evidence. First, genetic evolution within viral envelope sequences has been observed in a small number of treated patients with transient viremia. Second, unintegrated viral DNA and unspliced viral messenger RNA, both markers of recent cellular infection, are commonly detected in patients even after several years of effective therapy. Third, drug-specific mutations may emerge in cellular reservoirs of patients with undetectable or lowlevel plasma viremia. Fourth, patients with low-level viremia often have increasing amounts of replicationcompetent virus in cellular reservoirs. Thus, when viewed as a whole, it appears that viral replication persists in patients with low-level viremia, and that complete viral suppression is rarely achieved with current therapies. If antiretroviral therapy is only partially effective at suppressing viral replication, why were drug resistance muta-

Virological and Immunological Response to HAART Therapy in a Community-Based Cohort of HIV-1-Positive Individuals

Purpose: To determine virological and immunological response to highly active antiretroviral therapy (HAART) and to investigate factors influencing response in a community-based setting. Method: Plasma HIV RNA levels and CD4 cell counts were studied in 168 unselected individuals starting HAART including indinavir or ritonavir or hard-gel saquinavir-containing regimens. Results: Overall, 60% of the patients reduced their HIV RNA to below 500 Eq/mL, but half of them experienced a subsequent virologic rebound. Patients with higher baseline HIV RNA, higher baseline CD4 cell count, and simultaneous initiation of combination therapy and patients on indinavir or ritonavir regimen were more likely to have virologic response within 6 months since HAART initiation. Patients with lower baseline CD4 cell count and with lower rates of viral clearance had a higher probability of a subsequent virologic rebound. Forty percent of the patients had increased their CD4 cell counts by more than 100 cells/μL (immunologic response). The probability of immunologic response was independent of baseline HIV RNA levels and CD4 cell count; however, the more complete the virologic suppression, the higher the probability of immunologic response. Thirty percent of the patients had discordance between virologic and immunologic responses. Conclusion: The rate of virologic failure in this unselected group of patients was higher than that observed in randomized clinical trials, but only a minority (11%) of the patients were treatment naïve. Starting combination therapy simultaneously and initiating antiretroviral therapy before advanced HIV disease has developed predict virologic response, whereas the magnitude of viral suppression predicts mid to long immunological response.

Therapeutic drug monitoring as a tool in treating HIV infection.

Despite its success antiretroviral therapy (ART) is still associated with a significant risk of toxicity and subsequent virological failure. Pending the introduction of drugs with greater potency and durability one of the most pressing priorities in HIV treatment is to identify ways in which to maximize the efficacy of existing therapeutic options while minimizing its toxicity. Resistance testing has been shown to be one such strategy. Therapeutic drug monitoring (TDM) for HIV drugs has been widely proposed as another tool by which treatment may be optimized. There are some parallels with resistance testing not least the potential difficulties or pitfalls in interpreting test results and the understandable pressure for provision of this service in the face of increasingly limited treatment options notwithstanding the current lack of data from controlled clinical studies. In this reviews we shall discuss the value of TDM in the context of a ‘monitoring service (in other words drug concentrations are provided in conjunction with interpretation and advice) rather than a facility for ‘measuring drug concentrations. This distinction is important since the interpretation of drug concentrations is fraught with complexity. (excerpt)