Probability Of Virological Failure Research Articles

Impact of pre‐existent drug resistance on virological efficacy of single‐tablet regimens in people living with HIV

Despite the wide use of single-tablet regimens (STRs), few real-life data are available regarding the impact of pre-existent drug resistance on virological failure (VF). We aimed to fill this gap by analysing a large cohort of individuals selected from the ARCA database. The impact on VF of pre-existent resistance-associated mutations (RAMs) and cumulative genotypic susceptibility score (cGSS) before STR start was evaluated through survival analysis. Potential emergence of resistance at VF was also evaluated. Overall, 3916 individuals were included, comprising 678 treatment-naïve (G1), 2309 treatment-experienced aviraemic (G2) and 929 viraemic (G3), of whom 65.2% were treated with a STR based on efavirenz (35.2%) or rilpivirine (30.0%). At 2 years after starting a STR, the overall probability of VF was 5.9% in G1, 8.7% in G2 and 20.8% in G3. No impact of pre-existent resistance on VF was found in G1. The probability of VF was higher in patients with cGSS < 3 (reduced susceptibility to at least one drug) than in those with cGSS = 3 (full susceptibility to STR drugs) both in G2 and G3. A higher probability of VF was also found in the presence of pre-existent M184V (alone or in combination with pre-existent thymidine analogue mutations). Among patients who failed STR, a significant emergence of RAMs was found only in those exposed to EFV/FTC/TDF in G3 (specifically K103N and M184V). Our results confirm a high efficacy of STRs in clinical settings. Pre-existent resistance appears to influence virological efficacy of STRs in treatment-experienced individuals (both aviraemic and viraemic).

Long-term maintenance of virologic suppression in native and migrant HIV-1 naïve patients: an Italian cohort study

ABSTRACT Little is known about long-term maintenance of virologic suppression in HIV migrants in Italy. The study aims to compare virologic failure rates and associated factors among antiretroviral therapy (ART)-naïve migrants and natives enrolled in the ARCA database since 2007 who achieved virologic suppression within 18 months from the beginning of the ART. Kaplan-Meier method assessed the probability of virologic suppression and failure. Cox regression model was used for multivariate analysis. Of 2515 patients, 2020 (80.3%) were Italian, 286 (10.6%) migrants from low-income countries, of whom 201 (75.0%) from Africa, and 227 (9.0%) from high-income-countries. The median follow-up was 4.5 years (IQR 2.5–7). No difference was observed in the time of achievement of virological suppression in the three groups (log-rank: p = 0.5687). Higher probability of virologic failure was observed in Africans compared to Italians, to patients from high-income-countries and from low-income-countries other than Africans (Log-rank = p < 0.001). In the adjusted analysis, a higher virologic failure risk was found in Africans only compared to Italians. [HR 4.01; 95% CI 2.44–6.56, p < 0.001]. In Italy, African migrants are less likely to maintain virologic suppression compared to natives and other migrants. Targeted interventions could be needed for foreigners, especially for Africans.

A community-based model of HIV care for men who have sex with men and transgender women in Chicago

Socioeconomically disadvantaged men who have sex with men (MSM) and transgender women (TGW) share a disproportionate burden of the HIV epidemic. Providing care in the community may help improve retention and treatment outcomes of these clients. Our objective was to compare HIV outcomes between a community-based model (CBM) and a hospital-based model (HBM) of HIV care. This was a retrospective cohort study of MSM and TGW with HIV treated at community clinics or at a hospital-based clinic. The primary outcome was the cumulative probability of virologic failure (HIV viral load ≥200 copies/ml). We conducted multivariable Cox proportional hazard regression to identify differences in outcome by care setting. Of 258 MSM and TGW, approximately half received care in the CBM. They were more likely to be African American (71% versus 59%), uninsured (48% versus 39%), and used illicit drugs (40% versus 25%). There was no difference in virologic failure by setting (58% CBM, 53% HBM; cumulative incidence of virologic failure: 35% CBM, 25% HBM; adjusted HR = 1.11; 95% CI: 0.88–1.39). Despite serving clients at greater risk for failure, virologic failure in our CBM was similar to a traditional HBM for MSM and TGW living with HIV.

Long-term follow-up of HIV-infected patients on dolutegravir monotherapy.

In recent years, dolutegravir monotherapy has been explored as a drug-reduced regimen for HIV patients. This was a retrospective observational study, including patients virologically suppressed for ≥6 months, without previous virological failure (VF) under integrase inhibitors (INIs), who had been switched to dolutegravir monotherapy (50 mg/day). The primary aim was to report the proportion of VF at week 48 (W48) and week 96 (W96) of dolutegravir monotherapy. The evolution from baseline to W48 of residual viraemia on ultra-deep sequencing and HIV DNA was also evaluated. Sixty-one patients were included. Prior to switching to dolutegravir monotherapy, they had a median (IQR) of 15.4 (6.5-19.9) years of antiretroviral exposure, 5.8 (3.2-10.3) years of viral suppression and 687 (461-848) CD4+ cells/mm3. They remained on dolutegravir monotherapy for a median (IQR) of 100 (29-148) weeks. Forty-two out of 61 patients (68.9%) reached W48 and 32 out of 61 patients (52.5%) reached W96. VF occurred in three patients, with the emergence of INI resistance. VF occurred before W24 and in patients pre-exposed to INIs. At W48, the probability of VF (Kaplan-Meier analysis) was 5.6% (95% CI = 1.8%-16.4%). The same result was obtained at W96. Detectable residual viraemia did not increase and median HIV DNA did not change significantly (2.4 log/106 cells at baseline and 2.3 log/106 cells at W48). Dolutegravir plasma concentration was above the IC90 in 41/41 samples, from 22 patients. Long-term follow-up showed a low risk of VF under dolutegravir monotherapy, in a selected population of patients with previous long-term virological suppression and low HIV reservoir.

Physicians’ opinions on generic antiretroviral drugs and single-tablet regimen de-simplification for the treatment of HIV infection: a multicentre survey in Spain

To assess the attitudes and opinions about generic antiretroviral drugs (ARVs) and single-tablet regimen (STR) de-simplification among physicians prescribing HIV treatment in the cohort of the Spanish HIV/AIDS Research Network (CoRIS). An online questionnaire with 27 structured questions was sent to all physicians (n=199) who prescribed ARVs among the 45 centres participating in the cohort. A total of 169 (84.9%) physicians answered the questionnaire. Only 4.1% of the physicians would never prescribe generic ARVs, but 53.3% would not prescribe them if the number of pills per day increased and 89.3% would not prescribe them if the number of doses per day increased. However, 84.0% of the physicians agreed to prescribe generic ARVs if doing so would decrease costs for the public healthcare system. The percentages of physicians stating that generic ARVs (compared with branded ones) would be associated with worse adherence, more adverse effects or more probability of virological failure, provided that the number of pills and doses per day would not change, were low: 0.6%, 7.7% and 3.6%, respectively. However, these percentages were much higher if the generic ARV entailed breaking an STR: 63.9%, 18.9% and 42.0%, respectively. Most physicians stated that they needed more information about the effectiveness and safety of generic ARVs and the price difference compared with their branded equivalents. Although most physicians were confident about prescribing generic ARVs, the majority had strong concerns about de-simplifying STR, and they also needed more information about generic drugs.

No impact of previous NRTIs resistance in HIV positive patients switched to DTG+2NRTIs under virological control: Time of viral suppression makes the difference.

The accumulation of drug-resistance mutations on combined antiretroviral regimens (ART) backbone could affect the virological efficacy of the regimen. Our aim was to assess the impact of previous drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) on the probability of virological failure (VF) in patients, under virological control, who switched to dolutegravir (DTG)+2NRTIs regimens. All HIV-1 positive drug-experienced patients who started a regimen composed by DTG+2NRTIs [abacavir/lamivudine or tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)/emtricitabine (FTC)] in the ARCA collaborative group with HIV-RNA <50 cp/mL were included in the analysis. Patients with a previous VF to integrase inhibitors were excluded. The impact of single and combined NRTIs mutations on the probability of VF (defined as 2 consecutive HIV-RNA >50 copies/mL or one HIV-RNA >1000 copies/mL) was assessed by Kaplan Meier curves. A multivariable Cox regression analysis was constructed to assess factors potentially related to VF. Five hundred and eighty-eight patients were included in the analysis with a median time of viral suppression before the switch of 37 months (IQR 12–78), of whom 148 (25.2%) had at least one previous NRTIs resistance mutation. In the multivariable model no association was observed between NRTIs mutations and VF. Conversely, the duration of viral suppression before switch resulted associated with a lower risk of VF (for 1 month increase, adjusted Hazard Ratio 0.98, 95%CI 0.96–0.99; p=0.024). Previous NRTIs mutations appeared to have no impact on the risk of VF in patients switched to DTG+2NRTIs, whereas a longer interval on a controlled viremia decreased significantly the risk of VF.

Durability of switch regimens based on rilpivirine or on integrase inhibitors, both in association with tenofovir and emtricitabine, in HIV-infected, virologically suppressed patients

BackgroundSwitch strategies based on rilpivirine/tenofovir/emtricitabine or on an integrase inhibitor (InSTI) plus tenofovir/emtricitabine have never been compared in randomized clinical trials. The main aim of the study was to investigate the durability of these two switch regimens in virologically suppressed, HIV-infected patients.MethodsRetrospective analysis of patients who started rilpivirine or an InSTI (both with tenofovir and emtricitabine) with <50 HIV-RNA copies/mL and had at least one HIV-RNA assessed while receiving the study regimen. Virological failure (VF) was defined as two consecutive measurements of HIV-RNA >50 copies/mL. Treatment failure (TF) was define as either VF or discontinuation of any drug of the regimen. Durability was assessed by the Kaplan-Meier method and compared by Log-rank test. Residual viremia was defined as any detectable HIV-RNA below 50 copies/mL, as assed by a real-time PCR assay.ResultsSix hundred seventy-five patients (466 switched to a rilpivirine-, 209 switched to an InSTI-based regimen [18% dolutegravir, 39% raltegravir, 43% elvitegravir/cobicistat] were included in the analysis.The median (interquartile range, IQR) follow-up in the rilpivirine and in the InSTI group was 16.7 (8.8–22.2) and 10.4 (5.4–19.6) months. The 1-year cumulative probabilities (95%CI) of VF and TF were 0.97% (0.36%–2.62%) and 9.73% (7.21%–13.06%) in the rilpivirine group and 1.83% (0.57%–5.77%) and 8.75% (5.25%–14.4%) in the InSTI group, with no difference between groups (p = 0.328 and 0.209 for VF and TF). The proportion of time spent with residual viremia was comparable in the two groups (9% [IQR 0.5%–49%] and 17% [IQR 0.5%–50%] in the rilpivirine and in the InSTI group, p = 0.087).By the multivariable Cox regression model, TF was independently associated with being on therapy with a protease inhibitor vs. a non-nucleoside reverse transcriptase inhibitor at switch (AHR = 0.52; 95%CI = 0.31–0.90; p = 0.018), baseline total/HDL-cholesterol ratio (AHR = 1.19 per 0.5-units increments; 95%CI = 1.06–1.34; p = 0.004), baseline estimated glomerular filtration rate (AHR = 0.78 per 10-units increments; 95%CI = 0.67–0.90; p = 0.001) and baseline hemoglobin (AHR = 0.78 per 1-unit increments; 95%CI = 0.64–0.94; p = 0.009), but not with treatment group (rilpivirine vs. InSTI).ConclusionsIn our clinical practice, the durability of the two regimens was comparable and both showed a very low probability of VF.

Efficacy and tolerability of switching to a dual therapy with darunavir/ritonavir plus raltegravir in HIV-infected patients with HIV-1 RNA ≤50cp/mL.

Nucleos(t)ide reverse transcriptase inhibitors (NRTI) toxicity may represent a threat for long-term success of combined antiretroviral therapy. Some studies have suggested a possible improvement of NRTI-related toxicity after switching to NRTI-sparing regimens. We aimed to explore the efficacy and tolerability of switching to darunavir/ritonavir (DRV/r) plus raltegravir (RAL) while having a viral load (VL) ≤50 copies/mL in the clinical setting. Treatment-experienced HIV 1-infected patients enrolled in the ICONA Foundation Study cohort were included if they switched their current regimen to DRV/r+RAL with a HIV-RNA ≤50copies/mL. Different definitions of virological failure (VF) and treatment failure (TF) were employed. Kaplan-Meier curves and Cox regression models were performed to estimate time to event probability. We included 72 HIV-infected patients, 22 (31%) of these were female, 31 (43%) men who have sex with men (MSM) amd 15 (21%) had hepatitis co-infections. Median age was 44 (IQR: 35-50) years amd CD4 count was 389 (IQR 283-606) cells/mmc. Median follow-up time for TF was 24 (IQR 9-31)months. Twenty-five discontinuations occurred (60% simplifications); only 2 (8%) were toxicity-driven (lipid elevations). The probability of VF (confirmed VL >50 copies/mL) was estimated at 7% [95% confidence interval (CI) 1-13%] by 12 and 9% (95% CI 2-16%) by 24months. When considering TF, we found a probability of stop/intensification/single VL>200 copies/mL of 13% (95% CI 1-17%) and 22% (95% CI 11-33%) by 12 and 24months. Female gender (adjusted relative hazard, ARH=0.10; 95% CI 0.01-0.74; p=0.024) and older age (AHR=0.50 per 10years older; 95% CI 0.25-0.99; p=0.045) were associated with a lower risk of TF. A previous PI failure was strongly associated with TF (AHR=52.6, 95% CI 3.6-779; p=0.004). DRV/r+RAL is a valuable NRTI-sparing option, especially in female and older patients, with a relatively low risk of VF and good tolerability after 2years since start in an ART-experienced population. However, previous PI-failure should be a limiting factor for this strategy.

Efficacy and safety of a switch to unboosted atazanavir in combination with nucleoside analogues in HIV-1-infected patients with virological suppression under antiretroviral therapy

Limited data are available on the use of unboosted atazanavir in combination with nucleoside reverse transcriptase inhibitors (NRTIs) in treatment-experienced HIV-infected patients. We conducted a multicentre, retrospective study among patients with plasma HIV-1 RNA levels <50 copies/mL under antiretroviral therapy who switched to unboosted atazanavir + NRTIs between January 2002 and December 2008. Virological failure during follow-up was defined as a confirmed plasma HIV-1 RNA level >50 copies/mL. Baseline risk factors for virological failure were identified using Cox proportional hazards models. A total of 886 patients were analysed. At baseline, median age was 44 years, 71.5% were males and median CD4 cell count was 490 cells/mm(3). NRTIs used in combination with atazanavir were tenofovir, abacavir and emtricitabine/lamivudine in 36.9%, 44.1% and 94.4% of patients, respectively. Median follow-up was 21 months. The 3 year probability of virological failure was 20.1%. Only a history of virological failure under NRTIs [hazard ratio (HR) 1.63, P = 0.049] and under protease inhibitors (HR 2.04, P = 0.006) were significantly associated with the risk of virological failure. Among the 431 patients without a prior history of virological failure, the 3 year probability of virological failure was 11.3%, and only hepatitis C virus co-infection (HR 2.25, P = 0.026) and abacavir use (HR 0.43, P = 0.04) were associated with the risk of virological failure. Safety of the switch was satisfactory, with improvement of the lipid profile. In patients with virological suppression and no prior history of virological failure, a switch to unboosted atazanavir in combination with NRTIs is associated with a low probability of virological failure and a good safety profile.

Niveau de preuve du suivi therapeutique pharmacologique de la névirapine

Nevirapine, a HIV non nucleosidic reverse transcriptase inhibitor, displays an inter-individual variability in its pharmacokinetics parameters, related to its hepatic metabolism. Based on literature, is the nevirapine therapeutic drug monitoring relevant? In naïve and pre-treated HIV infected patients, the probability of achieving and maintaining an undetectable HIV viral load was significantly associated with a nevirapine plasma trough concentration (Ctrough) >4000 ng/mL. The probability of virologic failure was significantly associated with a Ctrough <3000 ng/mL. Concerning the exposure-toxicity relationship, the emergence of hepatotoxicity was more frequently associated with high Ctrough, especially in case of HCV coinfection. Non-randomized studies have reported the interest of nevirapine therapeutic drug monitoring to optimize the virologic response and, to a lesser extent, to prevent hepatotoxicity. Therefore, the level of evidence of the interest of nevirapine therapeutic drug monitoring is "recommended".

Impact of the Frequency of Plasma HIV-1 RNA Monitoring on the Outcome of Antiretroviral Therapy

Current guidelines for HIV management recommend monitoring plasma HIV-1 RNA level every 3-6 months in patients on a stable antiretroviral regimen. However, cost is the major obstacle to follow the guidelines in resource-limited settings. This study aimed to compare the outcome of antiretroviral therapy among HIV-infected patients on a stable regimen who had plasma HIV-1 RNA monitoring once vs. twice yearly. A retrospective cohort study was conducted among HIV-infected patients receiving antiretroviral therapy since 2002 at Chiang Mai University Hospital, Thailand. We evaluated the incidence of virological failure and number of reverse transcriptase (RT) mutations between groups. Of 551 patients on a stable antiretroviral regimen, 405 (73.5%) and 146 (26.5%) patients had plasma HIV-1 RNA measurement once and twice yearly, respectively. Forty-seven of 405 patients (11.6%) in once-yearly group and 15 of 146 patients (10.3%) in twice-yearly group developed virological failure, giving the incidence rate of 2.03/100 and 1.95/100 person-years, respectively. The probability of virological failure did not differ between groups (p=0.897, log-rank test). The number of RT mutations was not statistically different between groups (all p-values>0.05). The predicting factors for virological failure from a multivariate analysis were adherence rate <95% and baseline CD4 cell count <50 cells/mm3 but not the frequency of HIV-1 RNA monitoring. The incidence of virological failure and the number of RT mutations were not different between groups. Therefore, in resource-limited settings, the recommendation to perform plasma HIV-1 RNA measurement once yearly in patients on a stable antiretroviral regimen is justified.

Risk of Viral Failure Declines With Duration of Suppression on Highly Active Antiretroviral Therapy Irrespective of Adherence Level

To model the effect of adherence and duration of viral suppression on the risk of viral rebound. Viral rebound was defined as the first of at least two consecutive viral loads greater than 400 copies/mL after initial viral suppression. The main exposures were adherence, presence of antiretroviral class resistance before rebound or censoring date, and the percentage of follow-up time with viral suppression. A total of 274 (N = 1305 [21%]) individuals experienced viral rebound. Median time of suppression before rebound was 2 years. Viral rebound was less likely to occur among those with longer duration of continuous viral suppression (odds ratio, 0.37; 95% confidence interval, 0.32 to 0.42). Among individuals with moderate levels of adherence (80% to less than 95%), the probability of virologic failure was 0.85 after being suppressed for 12 months and it was 0.08 after 72 months being suppressed (P < 0.01). Individuals with drug resistance were at a higher risk of viral rebound. The risk of viral rebound decreased with longer duration of viral suppression within each of adherence strata studied. Although perfect adherence remains an important goal of therapy to prevent disease progression, individuals with long-term viral suppression may be able to miss more doses without experiencing viral rebound.

Effectiveness of highly active antiretroviral therapy (HAART) among HIV-infected patients in Mexico.

The National Government HAART Program (NGP) for the provision of HAART to uninsured HIV-infected persons in Mexico began in 2001. The objective was to describe the virologic outcome of patients enrolled in the NGP in a large HIV treatment center in Mexico City. HIV-infected persons, naive or < or =6 months on HAART, who entered the NGP from 2001 to 2005 were included. Patients with virological suppression were compared to those with virologic failure (VF) during follow-up. Of 377 patients enrolled, 191 where eligible for analysis. The median age was 35.9 (18-75 years) and 85% were male. The median baseline CD4(+) T cell count was 183 cells/mm(3); 63.9% had <200 cells/mm(3) and/or an AIDS-defining event. During follow-up (median: 17.77 months), 55 patients (28.7%) changed their first regimen: 8.3% because of VF and the remaining due to toxicity. The probability of VF at 48 months was 20%. VF was associated with age <30 years (p = 0.003, RR 4.7, IC 95% 1.5-14.4). The use of NNRTI was associated with lower risk of VF (p = 0.042, RR 0.3, IC 95% 0.12-0.99). Nadir CD4(+) and AIDS-defining at baseline were not associated with VF. Implementation of NGP for HAART access in a specialized care setting in Mexico resulted in an excellent virologic response. Younger age was a significant risk factor for VF.

Authors' response: the importance of asking the right question

Dear Sirs, We thank Drs Koole and Van den Ende for their comment on our recent study (Keiser et al. 2009). We analysed more than 2000 patients from antiretroviral treatment programmes in Africa and South America that routinely monitor both CD4 cell counts and viral load. We concluded that based on a low positive predictive value of the World Health Organization (WHO) immunological criteria (<30%), these should not be interpreted as indicating virological failure. On the other hand, if immunological criteria were not met, virological failure was highly unlikely: negative predictive values ranged from 88% to 99% depending on the definitions chosen. Surprisingly, Koole and Van den Ende felt that this was ‘a classical example of misuse of predictive values’. We suspect that they misunderstood the objective of our study. Three related questions are of interest: (i) How should CD4 counts be interpreted in a given setting, taking into account the relevant (pre-test) probability of virological failure? (ii) What is the ability of the CD4 count criteria to modify pre-test probabilities? (iii) Should CD4 counts be recommended to detect virological failure? We have worked for several years with antiretroviral treatment programmes that routinely monitor CD4 cell counts but do not have access to viral load testing, and we intended to provide guidance to these programmes (Braitstein et al. 2006; Keiser et al. 2008a). We, therefore, focussed on the first question and calculated predictive values. Based on these probabilities, few people would disagree with our advice that in these settings, the WHO immunological criteria are more appropriate for ruling out than for ruling in virological failure. The ability of the CD4 count criteria to modify pre-test probabilities (question 2) is best captured by likelihood ratios: the further away from one the ratio is, the greater the test result’s ability to modify the pre-test probability (Pewsner et al. 2004). These ratios are presented in Table 1. The ability of a given result to produce a sufficiently high or low post-test probability to rule in or rule out a condition does, however, also depend on the pre-test probability in that setting. For the treatment programmes included in our study, the likelihood ratio of a positive test would need to be very high to rule virological failure in (>200 to arrive at a post-test probability of 80%). In contrast, as we pointed out in our study, because the incidence of virological failure is low, the post-test probability of a negative test was high even with very modest negative likelihood ratios ranging from 0.59 to 0.90 (Table 1). Again, we were interested in the appropriate interpretation of CD4 counts in these settings and focussed on what ultimately matters: the predictive values or post-test probabilities. The third question is important, but it was not the focus of our analysis. We agree with Koole and Van den Ende that CD4 counts should not be measured to detect virological failure; however, CD4 counts also provide essential information on the eligibility for ART, the immunological response to ART and the short-term risk of toxicity, disease progression and death on ART. We concur with Koole and Van den Ende that further research is needed to better define the role of CD4 counts and viral load monitoring, particularly in the context of point of care tests for viral load. We believe such research will also be relevant to high-income settings where a more rational approach to monitoring could probably reduce costs without compromising the effectiveness of ART (Keiser et al. 2008b).

The Risk of Virologic Failure Decreases with Duration of HIV Suppression, at Greater than 50% Adherence to Antiretroviral Therapy

BackgroundWe hypothesized that the percent adherence to antiretroviral therapy necessary to maintain HIV suppression would decrease with longer duration of viral suppression.MethodologyEligible participants were identified from the REACH cohort of marginally housed HIV infected adults in San Francisco. Adherence to antiretroviral therapy was measured through pill counts obtained at unannounced visits by research staff to each participant's usual place of residence. Marginal structural models and targeted maximum likelihood estimation methodologies were used to determine the effect of adherence to antiretroviral therapy on the probability of virologic failure during early and late viral suppression.Principal FindingsA total of 221 subjects were studied (median age 44.1 years; median CD4+ T cell nadir 206 cells/mm3). Most subjects were taking the following types of antiretroviral regimens: non-nucleoside reverse transcriptase inhibitor based (37%), ritonavir boosted protease inhibitor based (28%), or unboosted protease inhibitor based (25%). Comparing the probability of failure just after achieving suppression vs. after 12 consecutive months of suppression, there was a statistically significant decrease in the probability of virologic failure for each range of adherence proportions we considered, as long as adherence was greater than 50%. The estimated risk difference, comparing the probability of virologic failure after 1 month vs. after 12 months of continuous viral suppression was 0.47 (95% CI 0.23–0.63) at 50–74% adherence, 0.29 (CI 0.03–0.50) at 75–89% adherence, and 0.36 (CI 0.23–0.48) at 90–100% adherence.ConclusionsThe risk of virologic failure for adherence greater than 50% declines with longer duration of continuous suppression. While high adherence is required to maximize the probability of durable viral suppression, the range of adherence capable of sustaining viral suppression is wider after prolonged periods of viral suppression.

Effectiveness of antiretroviral regimens containing abacavir with tenofovir in treatment-experienced patients: Predictors of virological response and drug resistance evolution in a multi-cohort study

In treatment-naïve patients, a combination antiretroviral therapy (cART) containing tenofovir (TDF) and abacavir (ABC) with lamivudine leads to unacceptably high virological failure rates with frequent selection of reverse transcriptase mutations M184V and K65R. We explored the efficacy of at least 16 weeks of ABC + TDF-containing cART regimens in 307 antiretroviral-experienced HIV-1-infected individuals included in observational databases. Virological failure was defined as an HIV RNA > 400 copies/ml after at least 16 weeks of treatment. Patients had received a median of three prior cART regimens. Of these, 76% concomitantly received a potent or high genetic barrier regimen (with at least one protease inhibitor [PI]) or non-nucleoside reverse transcriptase inhibitor or thymidine analogue) while a third non-thymidine nucleoside analogue was used in the remaining patients. The 1-year estimated probability of virological failure was 34% in 165 patients with HIV RNA > 400 copies/ ml at ABC + TDF regimen initiation. Independent predictors of virological failure were the absence of a potent or high genetic barrier cART, the higher number of cART regimens experienced, and the use of a new drug class. In the subset of 136 patients for whom there were genotypic resistance test results prior to ABC + TDF initiation, the virological failure (1-year estimated probability 46%) was independently predicted by the higher baseline viral load, the concomitant use of boosted PI, and the presence of reverse transcriptase mutation M41L. In 142 patients starting ABC + TDF therapy with HIV RNA pound < or =400 copies/ml, virological failure (1-year estimated probability 17%) was associated only with the transmission category. In a small subset of subjects for whom there were an available paired baseline and follow-up genotype (n = 28), the prevalence of most nucleoside analogue reverse transcriptase inhibitor resistance mutations decreased, suggesting a possible low adherence to treatment. No selection of K65R was detected. The virological response to ABC + TDF-containing regimens in this moderately-to-heavily treatment experienced cohort was good. Higher viral load and the presence of M41L at baseline were associated with worse virological responses, while the concomitant prescription of drugs enhancing the genetic barrier of the regimen conveyed a reduced risk of virological failure. The Appendix provides the names of other members of the MASTER cohort.

Emtricitabine is more effective than stavudine for combination therapy in people with HIV

QuestionIs emtricitabine as effective and safe as stavudine when taken with didanosine and efavirenz by people with HIV-1?Study designRandomised double-blind controlled trial.Main resultsEmtricitabine significantly increased the probability of a persistent virological response when compared with stavudine (interim analysis, median follow-up of 42 weeks: percentage of participants with <50 copies/ml: 85% for emtricitabine v 76% for stavudine, p=0.005. End-point analysis, median follow-up 60 weeks: 76% for emtricitabine v 54% for stavudine, p=0.001). At 42 weeks, people taking emtricitabine had significantly increased mean CD4 cell counts compared with stavudine (increase from baseline: 156 cells/μl for emtricitabine v 119 cells/μl for stavudine; p=0.01), although there were no significant difference between groups at 48 weeks (p=0.15). The probability of virological failure was significantly less in the emtricitabine group (4% for emtricitabine v 12% for stavudine; p=0.001). Adverse events leading to stopping treatment were lower with emtricitabine compared with stavudine (7% v 15%; p=0.005).Authors’ conclusionsEmtricitabine is a more effective virological agent, has a longer lasting response, and is better tolerated than stavudine when taken as a first-line treatment with didanosine and efavirenz by people with HIV-1. At the time of study, the emtricitabine/didanosine/efavirenz regimen was the only once daily highly active antiretroviral therapy available.

A randomized study of emtricitabine and lamivudine in stably suppressed patients with HIV

Once daily (QD) dosing facilitates regimen simplification and adherence to antiretroviral therapy. Emtricitabine (FTC) QD is a newly approved nucleoside reverse transcriptase inhibitor compared in this study to twice daily lamivudine (3TC BID). Controlled, open label equivalence trial of 440 HIV-1-infected patients with plasma HIV-1 RNA stably suppressed on a regimen of 3TC 150 mg BID, stavudine or zidovudine, and a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Patients were randomized to continue their current regimen or replace 3TC with FTC 200 mg QD. If HIV-1 RNA levels were </= pound 400 copies/ml at 48 weeks in Protocol 303, patients could continue on FTC in Protocol 350. The primary analysis was based on virologic failure and response defined by plasma HIV-1 RNA suppression below 400 copies/ml. At baseline, the mean CD4 cell count was 525 (FTC) and 533 x 10(6) cells/l (3TC). At week 48 in Protocol 303, the probability of virologic failure was low, 7% (FTC) and 8% (3TC), and the probability of sustained viral suppression at week 48 was equivalent between treatment arms at both the 50 and 400 copies/ml thresholds. The mean increase in CD4+ T-cell percentage was 2.5% (FTC) and 1.7% (3TC). In Protocol 350, the probability of virologic failure was 11% after 4 years on FTC-containing highly active antiretroviral therapy (HAART). In stably suppressed patients, 200 mg emtricitabine QD was equivalent to 150 mg lamivudine BID. Emtricitabine-containing HAART was associated with a high rate of sustained virologic suppression during 4 years of follow-up.

Switching from protease inhibitors to efavirenz: differences in efficacy and tolerance among risk groups: a case-control study from the Swiss HIV Cohort.

Many patients have simplified their therapy by replacing protease inhibitors (PI) with efavirenz. In a large cohort study representative of clinical practice, we compared outcomes in patients who replaced PI with efavirenz (switchers), with patients who continued on PI (non-switchers). We investigated the likelihood of virological failure in switchers and non-switchers, and the tolerance of efavirenz-containing regimens in different transmission risk groups. Using the database of the Swiss HIV Cohort Study, we identified patients who switched from PI-containing to efavirenz-containing highly active antiretroviral therapy for reasons of tolerance, toxicity, or convenience. Switchers were matched to non-switchers on the basis of calendar time, CD4 cell count, and viral load. The probability of virological failure was less in patients who switched to efavirenz values after one year: 9.4% [95% confidence interval (CI) 5.5-15.9] versus 27.2% (95% CI 21.5-34.1), odds ratio (OR) for failure 0.34. The effect was more pronounced when injection drug users (IDU) were omitted from the analysis (OR 0.19, 95% CI 0.09-0.43); it was absent in IDU (OR 0.95, 95% CI 0.44-2.04). IDU stopped efavirenz more frequently during the first 2 months of treatment than non-IDU [22.6% (95% CI 11.5-41.6) versus 6.6% (95% CI 3.6-11.8) at 2 months]. No difference between IDU and non-IDU was evident when the frequency of stopping indinavir or nelfinavir was measured. Switchers had less virological failure and less chance of further treatment changes than non-switchers. However, efavirenz was less successful in IDU than in other transmission categories.