Non-nucleoside Reverse Transcriptase Inhibitor Regimens Research Articles

Primera pauta de tratamiento antirretroviral en pacientes con infección por el virus de la inmunodeficiencia humana. Durabilidad y factores asociados a su modificación

To analyze the durability of the first highly active antiretroviral therapy (HAART) regimen used in naïve HIV-infected patients and the factors leading to therapy changes. Multicenter, retrospective study of naïve HIV-infected patients from 5 hospitals in Málaga (southeast Spain), who started HAART between January 1997 and December 2003. The main outcome measure was median time to the first change in the antiretroviral regimen. A descriptive analysis was performed and Kaplan-Meier curves were used to assess durability of the first HAART used. Independent factors associated with durability were evaluated with a Cox multiple regression model. A total of 603 patients started HAART, and 130 (21.6%) remained under the same treatment at the latest evaluation point. Median time on the same HAART was 17.5 months, and reached 24 months when cases of simplification or structured intermittent treatment interruption were excluded from the analysis. HAART had been interrupted in 36% by one-year of follow-up. Toxicity was the main cause of switching therapy (25%), followed by simplification (19%), and virologic failure (15%). Longer durability of HAART was observed in non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens, (P < 0.046; HR, 1.58) and in those with less than 5 pills (P < 0.001; HR, 2.05). Median durability of the first HAART was almost one year and a half, and discontinuation was mainly due to toxicity. NNRTI regimens showed longer durability, which could be attributable to a lower pill burden, at least in part.

Editorial Commentary:Understanding the Complications of Antiretroviral Drugs

<i>Editorial Commentary:</i>Understanding the Complications of Antiretroviral Drugs

What Conditions Affect Initial HIV Treatment Success?

Highly active antiretroviral therapy has substantially improved the outlook for persons with HIV, and the combination of clinical trial data and experience has provided guidance for the best use of highly active antiretroviral therapy to balance efficacy, safety, tolerability, and adherence. The nonnucleoside reverse transcriptase inhibitors (NNRTIs) and several of the boosted protease inhibitors (PIs, eg, lopinavir/ritonavir) have shown high levels of viral suppression and CD4 count increases as initial therapy. Preliminary evidence suggests that NNRTI regimens may be more forgiving of certain levels of nonadherence than PIs. The evidence also shows that not all agents or combinations of agents are appropriate for all HIV patients. Patient factors such as lipids and triglycerides, hyperglycemia/diabetes, renal function, weight, gender, probability of and desire for pregnancy, initial CD4 count, race, and mental health status will all need to be considered to select the best therapy for the individual.

Randomized open-label trial of two simplified, class-sparing regimens following a first suppressive three or four-drug regimen

Complex antiretroviral regimens can be associated with increased toxicity and poor adherence. Our aim was to compare the efficacy and safety of switching to two simplified, class-sparing antiretroviral regimens. We conducted a randomized, open-label study in 236 patients with virologic suppression who were taking a three- or four-drug protease inhibitor or non-nucleoside reverse transcriptase inhibitor regimen for > or = 18 months. Patients received lopinavir/ritonavir (LPV/r) 533 mg/133 mg twice daily + efavirenz (EFV) 600 mg once daily or EFV + two nucleoside reverse transcriptase inhibitors (NRTI). Primary study endpoint was time to first virologic failure (VF, confirmed HIV-1 RNA > 200 copies/ml) or discontinuation because of study drug-related toxicity. After 2.1 years of follow up, patients receiving LPV/r + EFV discontinued treatment at a greater rate than patients receiving EFV + NRTI (P < 0.001). Twenty-one patients developed VF (14 receiving LPV/r + EFV and seven receiving EFV + NRTI) and 26 discontinued because of a study drug-related toxicity (20 receiving LPV/r + EFV and six receiving EFV + NRTI). Time to VF or study drug related-toxicity discontinuation was significantly shorter for LPV/r + EFV than EFV + NRTIs (P = 0.0015). A significantly higher risk of drug-related toxicity occurred with LPV/r + EFV, mainly for increased triglycerides (P = 0021). A trend toward a higher VF rate occurred with LPV/r + EFV in an intent-to-treat and as-treated analyses (P = 0.088 and P = 0.063 respectively). Switching to EFV + NRTI resulted in better outcomes, fewer drug-related toxicity discontinuations and a trend to fewer virologic failures compared to switching to LPV/r + EFV.

Intermittent therapy for the treatment of chronic HIV infection

Intermittent therapy for the treatment of chronic HIV infection

Comparison of Single and Boosted Protease Inhibitor Versus Nonnucleoside Reverse Transcriptase Inhibitor–Containing cART Regimens in Antiretroviral-Naïve Patients Starting cART After January 1, 2000

Background: Few published studies have considered both the short- and long-term virologic or immunologic response to combination antiretroviral therapy (cART) and the impact of different cART strategies. Purpose: To compare time to initial virologic (<500 copies/mL) or immunologic (>200/mm3 cell increase) response in antiretroviral-naïve patients starting either a single protease inhibitor (PI; n = 183), a ritonavir-boosted PI regimen (&n = 197), or a nonnucleoside reverse transcriptase inhibitor (NNRTI)–based cART regimen (n = 447) after January 1, 2000, and the odds of lack of virologic or immunologic response at 3 years after starting cART. Method: Cox proportional hazards models and logistic regression. Results: After adjustment, compared to patients taking an NNRTI-regimen, patients taking a single-PI regimen were significantly less likely to achieve a viral load (VL) <500 copies/mL (relative hazard [RH] 0.74, 95% CI 0.54–0.84, p = .0005); there was no difference between the boosted-PI regimen and the NNRTI regimen (p = .72). There were no differences between regimens in the risk of >200/mm3 CD4 cell increase after starting cART (p > .3). At 3 years after starting cART, patients taking a single-PI–based regimen were more likely to not have virologic suppression (<500 copies/mL; odds ratio [OR] 1.60, 95% CI 1.06–2.40, p = .024), while there were no differences in the odds of having an immunologic response (>200/mm3 increase; p > .15). This model was adjusted for CD4 and VL at starting cART, age, prior AIDS diagnosis, year of starting cART, and region of Europe. Conclusion: Compared to patients starting an NNRTI-based regimen, patients starting a single-PI regimen were less likely to be virologically suppressed at 3 years after starting cART. These results should be interpreted with caution, because of the potential biases associated with observational studies. Ultimately, clinical outcomes, such as new AIDS diagnoses or deaths, will be the measure of efficacy of cART regimens, which requires the follow-up of a very large number of patients over many years.

High Rate Multiple Drug Resistances in HIV-Infected Patients Failing Nonnucleoside Reverse Transcriptase Inhibitor Regimens in Thailand, Where Subtype A/E is Predominant

The prevalence of drug resistance was determined among 64 HIV-infected Thai patients who were failed while receiving nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. Eighty-nine percent of patients had 1 or more NNRTI mutation resistances. Almost all patients had resistance to at least 1 nucleoside reverse transcriptase inhibitor (NRTI), and 42% had multiple-NRTI resistance.

British HIV Association (BHIVA) guidelines for the treatment of HIV‐infected adults with antiretroviral therapy (2006)

British HIV Association (BHIVA) guidelines for the treatment of HIV‐infected adults with antiretroviral therapy (2006)

Short Communication: Nonnucleoside Reverse Transcriptase Inhibitor Fold Change or Plasma Concentration as a Predictor of Virological Response over 48 Weeks in Highly Treatment Experienced HIV-Positive Individuals

The nonnucleoside reverse transcriptase inhibitors (NNRTI) have low genetic barriers to resistance. Resistance can sometimes be overcome by increasing drug exposure. We assessed factors associated with 48-week virological response in treatment-experienced individuals receiving NNRTI therapy including resistance testing results and plasma drug exposure. Of 62 individuals assigned a new NNRTI-based regimen following resistance testing therapy consisted of efavirenz in 35 (56%) and nevirapine in 27 (44%) individuals. NNRTI fold change (FC) was determined from resistance test at baseline and plasma drug concentration at week 4. Mean time weighted change from baseline VL was -0.68 log over 48 weeks. Significant associations with change from baseline VL included baseline VL and FC whereas plasma drug concentration was not associated. In this cohort of highly treatment-experienced individuals treated with NNRTI regimens, we did not observe a significant association between NNRTI plasma concentration and virological response.

Higher Virological Effectiveness of NNRTI-Based Antiretroviral Regimens Containing Nevirapine or Efavirenz Compared to a Triple NRTI Regimen As Initial Therapy in HIV-1-Infected Adults

Purpose: To compare outcomes of nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine or efavirenz versus abacavir-based regimens with a backbone of zidovudine and lamivudine as initial therapy of treatment-naive adults with HIV-1 infection in routine clinical care. Method: All patients starting their first antiretroviral therapy with any of the studied regimens from January 1999 to December 2002 were included in the analysis. Rates of viral suppression (HIV-RNA below 50 copies/mL) and discontinuation of any component of the regimen were compared at 48 weeks. Results: Fifty-one patients started with one of the two NNRTI-based regimens and 49 started with the triple nucleoside regimen (3-NRTI). After 48 weeks, more patients in the NNRTI regimens (76.5%) than in the 3-NRTI (51.1%) regimen achieved a HIV-1 RNA level below the limit of detection (<1.7 log10 copies/mL; p = .008). Time to change the antiretroviral regimen was shorter with 3-NRTI (median [range]: 234 [139-329] days) than with NNRTI (346 [0-756] days) (p = .0901). More withdrawals related to drug toxicity or intolerance occurred with the 3-NRTI-based regimen. Conclusion: In a routine clinical care setting, initial antiretroviral treatment with an NNRTI (nevirapine or efavirenz) plus zidovudine and lamivudine was virologically superior and safer than a 3-NRTI therapy (abacavir with the same NRTI backbone).

Triple nucleoside reverse transcriptase inhibitor‐ vs. nonnucleoside reverse transcriptase inhibitor‐containing regimens as first‐line therapy: efficacy and durability in a prospective cohort of French HIV‐infected patients

Based on the short-term results of the AIDS Clinical Trials Group (ACTG) A5095 trial, zidovudine (ZDV)/lamivudine (3TC)/abacavir (ABC) is no longer recommended as a first-line antiretroviral regimen. Data on the efficacy of this triple nucleoside reverse transcriptase inhibitor (NRTI) combination compared with the gold-standard nonnucleoside reverse transcriptase inhibitor (NNRTI) regimen could provide important information. Patients were selected from three prospective cohorts of patients who received first-line therapy with ZDV/3TC plus an NNRTI or ABC, started after January 1998. Immunovirological changes and the proportion of treatment discontinuations were compared between groups. Of the 380 patients, 190 started on ABC [the triple-NRTI group (3N)] and 190 on NNRTI. At baseline, there was no statistical difference between the NNRTI and 3N groups for age (mean=38 years), sex (66% male) or CD4 cell count (mean=305 cells/muL). Mean baseline plasma HIV-1 viral load (pVL) was higher in the 3N group (4.6 vs. 4.3 log10 HIV-1 RNA copies/mL: P<0.01). Lower and higher estimates of median pVL decrease at month 24 were 2.05 and 4.76 log10 copies/mL in the 3N group, and 1.73 and 4.31 log10 copies/mL in the NNRTI group (not significant). CD4 cell count evolution did not differ between groups. Treatment discontinuation occurred in 45% vs. 44% of patients in the NNRTI and 3N groups, respectively, after median durations of 9 and 4 months, respectively (P=0.02). In this prospective cohort, 3N and NNRTI regimens as first-line therapy produced similar immunovirological responses.

Cardiovascular disease in HIV-positive patients

Cardiovascular disease in HIV-positive patients

Should Non-Nucleoside Reverse Transcriptase Inhibitors be Combined?

In the treatment of HIV-infected patients, an urgent need exists for more conveniently dosed and better tolerated regimens with improved virological and immunological efficacy. Based on preclinical studies, the combination of two non-nucleoside reverse transcriptase inhibitors (NNRTIs) was considered to fulfill this. Several clinical studies, however, have shown different results with regard to mechanism of action, pharmacokinetics, efficacy and toxicity of dual NNRTI regimens. Combinations of two NNRTIs have shown additive or synergistic inhibitory effects on the HIV-1 reverse transcriptase activity and the viral replication of HIV-1 in vitro, although antagonistic effects have also been described. When nevirapine and efavirenz were administered in combination, the exposure to efavirenz was decreased due to induction of metabolism by nevirapine. When compared with single NNRTI regimens, dual NNRTI regimens showed similar but not superior results with regard to virological and immunological success in treatment-naive and pretreated HIV-1-infected patients. However, NNRTI-associated adverse events, such as clinical hepatitis, elevated liver enzymes, rash, central nervous system toxicity and psychiatric disorders, occurred more frequently when two NNRTIs were administered concomitantly. In conclusion, regimens with both nevirapine and efavirenz seem to result in similar antiviral and immunological efficacy with an increased incidence of adverse events compared with single NNRTI regimens. The combination of two NNRTIs is therefore less desirable than other available and effective treatment options.

Higher Rates of Viral Suppression with Nonnucleoside Reverse Transcriptase Inhibitors Compared to Single Protease Inhibitors Are Not Explained by Better Adherence

Background: Although evidence suggests that antiretroviral (ARV) regimens containing nonnucleoside reverse transcriptase inhibitors (NNRTIs) are superior to single-protease inhibitor (PI)-based regimens at suppressing viral load, it is unclear how much of the improved viral suppression is due to intrinsic drug potency versus higher levels of adherence to simpler regimens. We therefore examined adherence and viral suppression in NNRTI and single-PI regimens in a cohort of largely ARV-experienced participants by using objective measures of adherence. Method: Participants were recruited from the Research on Access to Care in the Homeless (REACH) Cohort and were included in the study if they were on single-PI-based or NNRTI-based highly active antiretroviral therapy (HAART) regimens for at least 3 months prior to study entry. Adherence was measured by unannounced pill counts at the participant's usual place of residence. The primary outcome was suppression of HIV viral RNA to <50 copies/mL. Results: Among 109 individuals who were followed for a median of 8.7 months, the odds of virologic suppression were approximately 8 times higher (p < .01) for participants on NNRTI-based regimens (n = 53) compared with those using single-PI-based regimens (n = 56) when controlling for adherence, as well as other potential confounders in a multivariable analysis. The only other independent predictors of viral suppression in multivariable modeling were ARV adherence (p < .01), CD4 nadir (p = .02), and continuous months on current regimen prior to the start of adherence monitoring (p < .01). There was no significant difference in adherence by unannounced pill counts in participants receiving NNRTI- versus single-PI-containing regimens. Conclusion: A higher proportion of individuals using NNRTI-based regimens had viral suppression when compared to those taking single-PI-containing regimens, and this association was not confounded by higher levels of adherence. These results suggest that improved viral suppression on NNRTI regimens compared to single-PI regimens is more closely associated with regimen potency than higher levels of adherence.

Sequencing to NRTI plus NNRTI-Only Combinations After Virological Failure of Protease Inhibitor-Based Combination HIV-1 Therapy

Purpose: To examine the success of sequencing to nucleoside reverse transcriptase inhibitor (NRTI) plus nonnucleoside reverse transcriptase inhibitor (NNRTI)-only combinations after virological failure of protease inhibitor (PI)-based combinations in NNRTI-naïve individuals. Method: This was an observational cohort study. Results: 171 patients were identified. The group was highly antiretroviral therapy-experienced with median cumulative NRTI and PI durations prior to change of 53 months and 21 months, respectively. The median CD4 count and viral load (VL) prior to change were 228 cells/mm3 and 24,500 copies/mL. Overall, 37.4% had a VL below the limit of detection (50 copies/mL) at 12 months (intention-to-treat analysis). Markers associated with success at 12 months were efavirenz (EFV) use, the use of three NRTI+NNRTI combinations, and abacavir (ABC) use. In multivariate analysis, use of EFV remained highly significant (relative hazard of virological success of nevirapine [NVP] vs. EFV = 0.39; p = .003), while ABC use became nonsignificant. A benefit from the use of three NRTI + NNRTI regimens was observed. Conclusion: NRTI plus NNRTI-only combinations performed poorly, however the superior outcomes of patients treated with EFV are consistent with findings in cohort studies. The suggestion of benefit in patients receiving three NRTIs in addition to either NVP or EFV deserves further study in randomized trials.

Sequencing to NRTI plus NNRTI-Only Combinations After Virological Failure of Protease Inhibitor-Based Combination HIV-1 Therapy

Purpose: To examine the success of sequencing to nucleoside reverse transcriptase inhibitor (NRTI) plus nonnucleoside reverse transcriptase inhibitor (NNRTI)-only combinations after virological failure of protease inhibitor (PI)-based combinations in NNRTI-naïve individuals. Method: This was an observational cohort study. Results: 171 patients were identified. The group was highly antiretroviral therapy-experienced with median cumulative NRTI and PI durations prior to change of 53 months and 21 months, respectively. The median CD4 count and viral load (VL) prior to change were 228 cells/mm3 and 24,500 copies/mL. Overall, 37.4% had a VL below the limit of detection (50 copies/mL) at 12 months (intention-to-treat analysis). Markers associated with success at 12 months were efavirenz (EFV) use, the use of three NRTI+NNRTI combinations, and abacavir (ABC) use. In multivariate analysis, use of EFV remained highly significant (relative hazard of virological success of nevirapine [NVP] vs. EFV = 0.39; p = .003), while ABC use became nonsignificant. A benefit from the use of three NRTI + NNRTI regimens was observed. Conclusion: NRTI plus NNRTI-only combinations performed poorly, however the superior outcomes of patients treated with EFV are consistent with findings in cohort studies. The suggestion of benefit in patients receiving three NRTIs in addition to either NVP or EFV deserves further study in randomized trials.

Switch studies: a review.

Many physicians and patients wish to switch from successful protease inhibitor (PI)-based regimens to alternative regimens, usually composed of a nonnucleoside reverse transcriptase inhibitor (NNRTI) or abacavir plus two nucleoside reverse transcriptase inhibitors (NRTIs). This reflects a desire to avoid or reverse the metabolic changes observed during long-term PI-based antiretroviral therapy; to alleviate PI-associated adverse effects; and to improve adherence by simplifying the regimen. Data from a number of randomized and cohort PI switch studies are reviewed. Overall, the results of these studies are mixed, perhaps because of limitations in study design, patient number and duration of follow-up. In most studies, the frequency of virological failure is reduced by switching to a NNRTI regimen. Switching to an abacavir-based regimen is associated with two-fold higher risk of virological failure if mutations in the reverse transcriptase gene pre-exist. Improvements in metabolic and lipid abnormalities have not been uniform but favourable lipid changes have been reported, particularly after switching to nevirapine. Resolution of lipodystrophy symptoms has not been demonstrated objectively, perhaps because of insufficient follow-up and/or the role of NRTIs in this syndrome.

Cost effectiveness of combination HIV therapy: 3 years later.

Since 1997, expert panel guidelines for HIV care have recommended the use of combination antiretroviral therapy with at least 3 antiretroviral drugs. Several studies have examined the cost effectiveness of 3-drug combination antiretroviral regimens for the treatment of HIV infection. Analyses comparing a 3-drug protease inhibitor-containing regimen with a 1- or 2-drug non-nucleoside reverse transcriptase inhibitor regimen have consistently yielded incremental direct cost estimates ranging from $US10,000 to just over $US13,000 per year of life saved. In Western societies, such an incremental cost per year of life saved compares favourably with chronic therapy for other diseases and argues for the adoption of these drugs by payors and policy makers. The reason for this favourable cost-effectiveness ratio appears to be the decrease in opportunistic complications and hospitalisation associated with the effective use of combination antiretroviral therapy. Whether this initial benefit will be maintained is not yet known. Other comorbid illnesses such as hepatitis C or renal failure may subsequently increase the cost of HIV care, and some analyses suggest that resistance may develop to these drugs over the long term. In addition, studies are needed to assess the cost effectiveness of these therapies in developing countries where the expense of these drugs appears to put them out of reach. The collection and analysis of economic data will continue to be needed as newer HIV therapies become available and the HIV healthcare environment evolves. Quantifying medical care costs and calculating cost effectiveness involve assessing a moving target. Economic analyses of HIV infection must evolve in tandem with therapeutic changes to continue to be relevant to policy makers, payors of care, and those who provide and receive HIV care.