Early Virological Failure Research Articles

Early Virologic Failure in a Pilot Study Evaluating the Efficacy of Therapy Containing Once-Daily Abacavir, Lamivudine, and Tenofovir DF in Treatment-Naive HIV-Infected Patients

Previous investigational data using abacavir (ABC), lamuvidine (3TC), and zidovudine has suggested the possibility of triple nucleoside analogue reverse transcriptase inhibitors (NRTI) therapy as an option in the treatment of HIV infection. We performed a pilot study to assess the potency of once daily ABC+ 3TC+ tenofovir (TDF) in the treatment of HIV-infected naive patients. CD4 and HIV-viral load (VL) were followed monthly. Patients were considered to be nonresponder/failing if there was no reduction in VL by >/= 2 log(10) by week 8 and/or a rebound in VL after initial suppression. Resistance testing was then obtained. Nineteen patients naive to antiretroviral therapy (3 women and 16 men) were enrolled, of whom, 2 did not return (withdrew from study at week 2). Median VL and CD4 count at baseline were 147,167 copies per milliliter (5.16 log(10); [range, 7650->750,000]) and 277 cells/mm(3) (range, 59-598). Eight patients had VL > 100000 at baseline. Of 17 patients eligible for follow-up, 5 (27%) were responders (virologic success). Twelve patients (63%) were considered nonresponders and/or with virologic failure. The study was prematurely interrupted because of a high rate of treatment failure. Resistance testing available for 11 nonresponders (58%) showed: 2 patients with wild-type, 5 patients with M184V (reducing susceptibility to 3TC and ABC), 4 patients with M184V+K65R (K65R is responsible for reducing susceptibility to ABC, 3TC and TDF), and none with K65R alone. In conclusion, the combination of ABC, 3TC and TDF cannot be recommended for the initial regimen in HIV treatment-naive patients.

Assessment of CD8 T cell immune activation markers to monitor response to antiretroviral therapy among HIV-1 infected patients in Côte d'Ivoire.

Because of the paucity of plasma HIV RNA viral load (VL) tests in resource-poor settings, the CD4(+) T cell count is often used as the sole laboratory marker to evaluate the effectiveness of antiretroviral therapy (ART) in HIV-infected patients. In untreated patients, the level of activated T cells is positively correlated with VL and represents a prognostic marker of HIV infection. However, little is known about its value to predict early drug failure, taking into account the relatively high non-specific immune activation background observed in many resource-limited tropical countries. We assessed the use of immune activation markers (expression of CD38 and/or human leucocyte antigen-DR on CD8(+) lymphocytes) to predict virological response to ART in a cohort of HIV-1 infected patients in Abidjan, Côte d'Ivoire. Correlations between VL, absolute CD4(+) T cell counts and immune activation levels were examined in 111 HIV patient samples at baseline and after 6 and 12 months of therapy. The percentage of CD38(+) CD8(+) T cells appeared to be the best correlate of VL. In contrast, changes in CD4(+) T cell counts provided a poor correlate of virological response to ART. Unfortunately, CD38(+) CD8(+) percentages lacked specificity for the determination of early virological drug failure and did not appear to be reliable surrogates of RNA viral load. CD38(+) CD8(+) T cell percentages may, rather, provide a sensitive estimate of the overall immune recovery, and be a useful extra laboratory parameter to CD4 counts that would contribute to improve the clinical management of HIV-infected people when VL testing facilities are lacking.

Early virological failure in treatment-naive HIV-infected adults receiving didanosine and tenofovir plus efavirenz or nevirapine

A 50% rate of early virological failure associated with the selection of resistance mutations was seen in a group of 14 antiretroviral-naive adults who initiated highly active antiretroviral therapy with tenofovir and didanosine plus efavirenz or nevirapine. At month 6, the mutations detected were K65R, L74V, L100I, K103N/R/T, Y181C and G190E/Q/S. These results argue against the use of tenofovir plus didanosine in HIV-infected antiretroviral-naive adults even when the third drug is a non-nucleoside reverse transcriptase inhibitor.

Early Virological Failure with a Combination of Tenofovir, Didanosine and Efavirenz

To describe the occurrence of a high early virological failure (VF) rate and development of resistance mutations in antiretroviral-naive patients receiving tenofovir, didanosine and efavirenz. HIV-infected antiretroviral-naive patients with viral load > or =30 000 copies/ml were enrolled in a pilot randomized trial of tenofovir/didanosine (250 mg)/ efavirenz with (arm A) or without (arm B) lopinavir/r for the first 12 weeks. As six cases of early VF (a drop of <2 log at month 3, or a rebound of >1 log from the nadir) were detected (five in arm B and one in arm A who had previously stopped lopinavir/r) an unplanned interim analysis was performed. A total of 29 out of 36 enrolled patients completed at least 3 months of follow-up and were included in the interim analysis. An intent-to-treat analysis showed treatment failure in 7/15 (46.7%) patients in arm B (five VF, one lost, one switched) versus 2/14 (14.3%) in arm A (one lost, one switched) (P=0.109). The patient in arm A who interrupted lopinavir/r at day 3 and continued with tenofovir/didanosine/efavirenz later developed VF. At baseline, 6/6 VF patients had VL >100000 copies/ml and an advanced stage of disease (CD4 <200 plus CDC stage C or B3) versus 0/8 non-VF patients taking the triple drug regimen (P<0.001). At failure, G190S/E alone or associated with K103N and K101R mutations was detected in five patients, and K103N/L1001/V108l in the sixth patient. Additionally, L74V/I and K65R were detected in four and two patients, respectively. A high early virological failure rate and the occurrence of resistance mutations were detected in a group of antiretroviral-naive patients treated with tenofovir/didanosine/efavirenz.

Higher efavirenz concentrations determine the response to viruses carrying non-nucleoside reverse transcriptase resistance mutations

We examined the influence of both efavirenz plasma concentrations and non-nucleoside reverse transcriptase (NNRTI) resistance mutations on the antiviral activity of efavirenz in patients experiencing early virological failure under nevirapine-containing regimens. Up to 41% of patients reach less than 50 copies/ml at 48 weeks. No association was found between the presence of NNRTI resistance mutations and virological outcome. Nevertheless, patients responding virologically and carrying NNRTI-resistant viruses had higher efavirenz levels than those who did not respond.

Predictors of selection of K65R

Over the past 5 years, 1846 HIV-infected patients underwent drug resistance testing at our institution. None out of 216 drug-naive subjects showed K65R. However, it was recognized in 53 out of 1630 antiretroviral-experienced patients (3.3%), of whom 10 had never been exposed to tenofovir. The rate of K65R increased from 0.6% in 1999 to 11.5% in 2004. The recognition of K65R correlated negatively with the presence of thymidine analogue mutations but positively with Q151M.

Long-Term Virological Response to Multiple Sequential Regimens of Highly Active Antiretroviral Therapy for HIV Infection

Information about the virological response to sequential highly active antiretroviral therapy (HAART) for HIV infection is limited. The virological response to four consecutive therapies was evaluated in the Swiss HIV Cohort. Retrospective analysis in an observational cohort. 1140 individuals receiving uninterrupted HAART for 4.8 +/- 0.6 years were included. The virological response was classified as success (<400 copies/ml), low-level (LF: 400-5000 copies/ml) or high-level failure (HF: >5000 copies/ml). Potential determinants of the virological response, including patient demographics, treatment history and virological response to previous HAART regimens were analysed using survival and logistic regression analyses. 40.1% failed virologically on the first (22.0% LF; 18.1% HF), 35.1% on the second (14.2% LF; 20.9% HF), 34.2% on the third (9.9% LF; 24.3% HF) and 32.7% on the fourth HAART regimen (9% LF; 23.7% HF). Nucleoside pre-treatment (OR: 2.34; 95% CI: 1.67-3.29) and low baseline CD4 T-cell count (OR: 0.79/100 cells rise; 95% CI: 0.72-0.88) increased the risk of HF on the first HAART. Virological failure on HAART with HIV-1 RNA levels exceeding 1000 copies/ml predicted a poor virological response to subsequent HAART regimens. A switch from a protease inhibitor- to a non-nucleoside reverse transcriptase inhibitor-containing regimen significantly reduced the risk of HF. Multiple switches of HAART did not affect the recovery of CD4 T lymphocytes. Multiple sequential HAART regimens do not per se reduce the likelihood of long-term virological suppression and immunological recovery. However, early virological failure increases significantly the risk of subsequent unfavourable virological responses. The choice of a potent initial antiretroviral drug regimen is therefore critical.

Indinavir plasma concentrations and resistance mutations in patients experiencing early virological failure.

Virological failure under protease inhibitor (PI)-based antiretroviral regimens is often not explained by the selection of resistance mutations. The role of low indinavir (IDV) plasma levels in treatment failure was assessed in 46 subjects experiencing early virological failure to a first-line IDV-containing triple combination. Overall, 69% of patients showed subtherapeutic IDV plasma levels (it was not detected at all in 75% of them). Subjects with detectable but suboptimal IDV levels developed more IDV resistance mutations. Thus, drug monitoring may be useful to assess treatment adherence and risk of drug resistance in early virological failures. This information may be crucial for choosing the most appropriate rescue intervention.

Does an Increase in Nevirapine Plasma Levels Cause Complete Virologic Suppression in Patients Experiencing Early Virologic Failure?

Background: Patients on two nucleoside analogs plus nevirapine (NVP) who show low-level plasma HIV RNA might have insufficient NVP plasma levels and therefore might benefit from an increase in NVP dosing. Method: The dose of NVP was increased from 400 mg/day to 600 mg/day in 25 participants taking NVP-containing triple combinations for at least 3 months and experiencing a first virological failure (>50 HIV RNA copies/mL). The levels of NVP were measured in plasma samples taken prior to and 3 months after the intervention. HIV genotyping was performed at the time of dose increase. A control group of 25 participants who showed early virological failure with NVP continued with standard doses of the drug for 3 months. Results: The median HIV RNA and CD4 cell counts were 100 copies/mL and 635 cells/mm3, respectively. Similar figures were recorded in the control arm. Mean NVP plasma levels that were reached with a dose of 600 mg/day were significantly higher than those with 400 mg/day (7.4 μg/mL [5% CI, 6.4-8.4] vs. 3.4 μg/mL [95% CI, 2.9-3.9]; p < .0001). Thirteen (52%) participants reached <50 HIV RNA copies/mL after the intervention. The greater levels of NVP were relatively well tolerated, with no development of rashes and only mild elevations in transaminase levels. NVP-associated mutations were recognized in 9 of 10 participants who did not respond but only in 3 of 9 responders (p = .019). More frequent mutations appeared at positions 181, 103, 106, and 190. The levels of NVP did not change significantly in participants who were included in the control arm, and only one reached complete virological suppression after continuing treatment for 3 additional months. Conclusion: An increase of one pill of NVP per day led to a significant rise in NVP plasma levels. A greater virologic response was noticed among participants with higher NVP plasma levels. Major resistance mutations that conferred resistance to NVP were recognized in all participants who failed to regain virological suppression after increasing NVP dose.

Does an Increase in Nevirapine Plasma Levels Cause Complete Virologic Suppression in Patients Experiencing Early Virologic Failure?

Background: Patients on two nucleoside analogs plus nevirapine (NVP) who show low-level plasma HIV RNA might have insufficient NVP plasma levels and therefore might benefit from an increase in NVP dosing. Method: The dose of NVP was increased from 400 mg/day to 600 mg/day in 25 participants taking NVP-containing triple combinations for at least 3 months and experiencing a first virological failure (>50 HIV RNA copies/mL). The levels of NVP were measured in plasma samples taken prior to and 3 months after the intervention. HIV genotyping was performed at the time of dose increase. A control group of 25 participants who showed early virological failure with NVP continued with standard doses of the drug for 3 months. Results: The median HIV RNA and CD4 cell counts were 100 copies/mL and 635 cells/mm3, respectively. Similar figures were recorded in the control arm. Mean NVP plasma levels that were reached with a dose of 600 mg/day were significantly higher than those with 400 mg/day (7.4 μg/mL [5% CI, 6.4-8.4] vs. 3.4 μg/mL [95% CI, 2.9-3.9]; p < .0001). Thirteen (52%) participants reached <50 HIV RNA copies/mL after the intervention. The greater levels of NVP were relatively well tolerated, with no development of rashes and only mild elevations in transaminase levels. NVP-associated mutations were recognized in 9 of 10 participants who did not respond but only in 3 of 9 responders (p = .019). More frequent mutations appeared at positions 181, 103, 106, and 190. The levels of NVP did not change significantly in participants who were included in the control arm, and only one reached complete virological suppression after continuing treatment for 3 additional months. Conclusion: An increase of one pill of NVP per day led to a significant rise in NVP plasma levels. A greater virologic response was noticed among participants with higher NVP plasma levels. Major resistance mutations that conferred resistance to NVP were recognized in all participants who failed to regain virological suppression after increasing NVP dose.

Mechanisms of early virologic failure in antiretroviral-naive patients starting protease inhibitor-containing regimens: the APROVIR Study.

The virologic and pharmacologic mechanisms of virologic failure (VF) were studied in 243 antiretroviral-naive patients starting first-line protease inhibitor (PI)-containing therapy (nelfinavir in 66% and indinavir in 19%). Among the 220 patients with follow-up data, VF occurred in 35 (16%) during the first year of follow-up. A higher baseline virus load and poorer adherence to therapy were associated with VF. At the time of VF, key PI-resistance mutations were detected in 11 (48%) of 23 patients who started on nelfinavir but were absent in 6 patients with indinavir treatment failure. PI plasma levels were more often below the range of active concentrations in VF with wild-type viruses (74%) than in VF with PI-resistant viruses (25%; P=.02). The mechanisms of early VF and of selection of PI-resistant viruses differed by type of PI and were dependent on PI plasma levels.

Drug resistance in patients experiencing early virological failure under a triple combination including indinavir.

To assess the pattern of drug resistance mutations selected in HIV-1-infected patients failing a first line triple combination therapy including indinavir. Plasma samples from 87 patients collected at the time of the first virological rebound (> 50 HIV-RNA copies/ml) were examined for the presence of drug-resistant genotypes. The mean level of plasma viraemia at rebound was 7824 HIV-1 RNA copies/ml in 73 subjects with good compliance, whereas it was 359,460 HIV-1 RNA copies/ml in 14 patients who admitted to poor adherence. Genetic sequence analysis yielded results for 51 (70%) of the patients having good adherence. More than half of them (26/51, 51%) carried primary mutations associated with resistance to nucleoside analogues. In contrast, primary protease inhibitor resistance mutations were recognized less frequently (14/51, 27%; P < 0.05). Moreover, in 23 (45%) patients there was no evidence of drug-resistant viruses at all. The most frequent drug-resistant genotypes in the reverse transcriptase gene were at codons 184 (n = 19), 215 (n = 14) and 41 (n = 8), whereas for the protease they were at codons 46 (n = 10), 82 (n = 9) and 90 (n = 7). No resistance genotypes were found among non-compliant patients. The overall rate of drug-resistant HIV genotypes was 38% (28/73) in patients with good adherence and who were experiencing a first virological failure under a triple combination regimen including indinavir; resistance to nucleoside analogues was more frequent than resistance to indinavir. Therefore, treatment intensification in those patients without resistance, or a selective substitution of nucleosides in those with resistance limited to these compounds, might be justified.

Loss of antiretroviral drug susceptibility at low viral load during early virological failure in treatment-experienced patients

Clinical studies have demonstrated a correlation between the response to second-line antiretroviral therapy and the number of drugs in the regimen to which the virus is susceptible. These studies have largely been performed in patients with viral loads over 1000 copies/ml. To examine the evolution of resistance during early virological failure, and the potential role of susceptibility testing in patients with low viral loads (below 1000 copies/ml), in treatment-experienced patients. Drug susceptibility and genotypes of HIV-1 from indinavir-experienced patients undergoing therapy with nelfinavir, saquinavir, abacavir and either a second nucleoside reverse transcriptase inhibitor (NRTI) or nevirapine were determined. Sixteen subjects were studied. Five of the ten subjects treated with nevirapine, and one of six treated with a second NRTI, achieved and maintained plasma HIV RNA < 500 copies/ml. Virus from the treatment failures lost susceptibility to one or more treatment drugs, including nelfinavir and/or saquinavir, after 4 to 36 weeks of treatment. In six of the ten failures, virus with new reductions in drug susceptibility was detected prior to failure. In five of the six failures who had at least one plasma sample with a viral load between 50 and 1000 copies/ml, reductions in susceptibility to one or more treatment drugs were detected (viral load range: 260 to 630 copies/ml). Drug resistance can be detected at viral loads below 1000 copies/ml which may be predictive of treatment failure. Failure of a second line regimen was typically associated with early evolution of resistance in HIV protease.

Considerations in choosing a primary endpoint that measures durability of virological suppression in an antiretroviral trial.

At present, many clinical trials of anti-HIV-1 therapies compare treatments by a primary endpoint that measures the durability of suppression of HIV-1 replication. Several durability endpoints are compared. Endpoints are compared by their implicit assumptions regarding surrogacy for clinical outcomes, sample size requirements, and accommodations for inter-patient differences in baseline plasma HIV-1-RNA levels and in initial treatment response. Virological failure is defined by the non-suppression of virus levels at a prespecified follow-up time T(early virological failure), or by relapse. A binary virological failure endpoint is compared with three time-to-virological failure endpoints: time from (i) randomization that assigns early failures a failure time of T weeks; (ii) randomization that extends the early failure time T for slowly responding subjects; and (iii) virological response that assigns non-responders a failure time of 0 weeks. Endpoint differences are illustrated with Agouron's trial 511. In comparing high with low-dose nelfinavir (NFV) regimens in Agouron 511, the difference in Kaplan-Meier estimates of the proportion not failing by 24 weeks is 16.7% (P = 0.048), 6.5% (P = 0.29) and 22.9% (P = 0.0030) for endpoints (i), (ii) and (iii), respectively. The results differ because NFV suppresses virus more quickly at the higher dose, and the endpoints weigh this treatment difference differently. This illustrates that careful consideration needs to be given to choosing a primary endpoint that will detect treatment differences of interest. A time from randomization endpoint is usually recommended because of its advantages in flexibility and sample size, especially at interim analyses, and for its interpretation for patient management.