Many countries engaged in rapid antiretroviral scale-up activities since 2004 are now updating HIV treatment guidelines. New guideline recommendations primarily reflect the benefit of earlier initiation of antiretroviral therapy (ART) and the removal of stavudine (D4T) from preferred first-line regimens.1 Nevirapine (NVP) has been widely used in antiretroviral scale up programs mainly as a result of its cost in comparison to efavirenz (EFV) and the availability of NVP in inexpensive fixed-dose combinations by various generic manufacturers. Recent pricings for a 2-pill fixed-dose combination of azidothymidine (AZT)/lamivudine (3TC)/NVP costs $11.22 per month but a 3 pill regimen of TDF/3TC (combination) + NVP now costs $11.88 per month for adults.2 To conform with international guideline recommendations1 and with increasing accessibility of tenofovir (TDF), more use of TDF in combination with NVP is anticipated for first-line treatment.3 A generic fixed-dose combination of EFV with TDF/3TC is now available. A 2-pill regimen of TDF/3TC (combination) + EFV now costs $13.55 per month for adults. The difference in the cost of first-line regimens is primarily associated with the cost of EFV $4.25 per month compared with NVP $2.58 per month, which equates to a difference of $20 a year.2
However, large randomized clinical trials comparing the combination of TDF and NVP with the more widely studied combination of TDF and EFV have not been performed.4 There are no obvious reasons why the combination of TDF and NVP should not be highly active, and several prospective clinical trials have shown efficacy.5–16 Yet 2 small studies comprising less than 42 patients did suggest that the combination of TDF + NVP and emtricitabine or lamivudine (XTC) has higher virologic failure rates than anticipated.17–19 Despite the lack of difference in the primary endpoints between the NVP/TDF/emtricitabine (FTC) and the atazanavir/r + TDF + FTC arms in the ARTEN trial, there were more participants in the NVP arms than the atazanavir/ritonavir arm who discontinued study drugs because of adverse events (13.6% vs. 2.6%) or lack of efficacy (8.4% vs. 1.6%).11 The 2011 US DHHS guidelines list NVP as an acceptable but not a preferred or an alternative first-line drug and continue to place a warning on combination of NVP and TDF.20 There is also conflicting data, mostly from cohort studies that suggest EFV regimens in general are more efficacious than NVP-based regimens.21–27 The large 2NN study where patients were randomized to NVP or EFV found no significant differences in viral suppression among study groups, but showed significantly higher rates of adverse events in the NVP arms compared with the EFV arms.27
In our program, our data collection tools did not distinguish between FTC and 3TC. When used in combination with TDF, these drugs were at times interchangeably used based on accessibility of fixed-dose combinations, thus although the majority of patients were treated with 3TC, we will refer to 3TC or FTC as (XTC) in the analysis. Without randomized prospective trials to directly compare TDF/XTC/EFV to TDF/XTC/NVP,28 we aimed to determine viral outcomes from an observational cohort of patients treated on current WHO recommended first-line regimens in resource-limited settings.
AIDSRelief Clinical Data Set
The AIDSRelief (AR) program is a President's Emergency Plan for AIDS Relief–supported care and treatment program. The AR program initiated antiretroviral treatment in 8 resource-limited countries in June of 2004. By August 31, 2011, more than 300,000 patients had received ART in more than 300 treatment facilities. Since 2005, the AR program has conducted an on-going annual patient level outcome review as a continuous quality improvement effort in selected countries and facilities able to participate. Information gathered is used to improve quality of clinical care provided at individual treatment clinics. With national institutional review board approvals, patients are randomly selected from a list of all patients who initiated ART within a specified program year. To be included, patients must have started ART at least 9 months before randomization. Using standardized data abstraction tools, the medical charts of all selected patients are reviewed for relevant clinical information including laboratory results, regimen switches, adverse events, opportunistic infections, death, and lost to follow-up. Patients who are alive and still on treatment also receive a viral load measurement and a validated adherence survey. The adherence survey collects information on adherence to HIV treatment, disease knowledge, barriers to adherence such as drug and alcohol use, symptoms of depression, and perceived quality of services.
Patient data sets were compiled on a total of 10,040 adult patients who initiated ART between June 2004 and January 2010. These patients were being treated in 61 health facilities in Kenya, Uganda, Zambia, and Nigeria. These were the only countries in the AR program using TDF-based regimens at the time of this review. Eligible patients were aged 16 or older and could have any baseline CD4 count. Baseline viral loads were not routinely collected. Patients were included in the analysis if they were treated with AZT/3TC/NVP, TDF/XTC/NVP, AZT/3TC/EFV, or TDF/XTC/EFV as their first regimen once enrolled in the AR program. Not all patients in this cohort were naive to ART at entry into the AR program. Patients were included in the analysis who may have been previously exposed to antiretroviral drugs, including single-dose NVP, but received a first-line regimen on enrollment into the AR program. Such patients could have initiated combination ART before enrollment and continued on the same or an equivalent regimen once enrolled in the program. We defined “poor adherence” by combining both a self-report of missing 1 or more ART doses in the month before viral load analysis and missing 1 or more clinic appointment in the preceding 3 months.29
Although our study is a retrospective review of patient charts along with a 1-time cross-sectional viral load measurement and adherence survey, we attempted to approximate the conditions of a clinical trial. Our primary outcome was the proportion of patients with HIV viral load suppression less than 400 copies per milliliter. The primary analysis included only patients who were still on their initial first-line regimen at time of cross-sectional patient-level outcome review, regardless of length of time on therapy as long as that exceeded 9 months, representing an on-treatment (OT) analysis.
An intention to treat (ITT) viral suppression outcome was conducted as a secondary analysis. Patients switching or changing ART for any reason before the time of patient-level outcome review were considered as having failed. In this analysis, a switch could have occurred for reasons such as toxicity, side-effect, pill burden, clinical or immunological failure, viral failure before patient-level outcome review, tuberculosis (TB), pregnancy, stock out, provider, or patient preference. Patients who died or were lost to follow-up (defined as having no contact with the clinic for 3 consecutive months and who could not be located on 3 consecutive attempts by clinic personnel), stopped treatment for any reason, or who were recorded to have “transferred out” were also considered failures. Patients who were on therapy at the time of cross-sectional review, but were unable to obtain a viral load sample, were also considered failures, representing an intent to treatment analysis [ITT, missing = failure (M = F), antiretroviral switch = failure (S = F)].
In an additional analysis, we only included patients with well-defined and clinically relevant reasons for treatment failure with the aim of arriving at a more clinically useful comparison of the regimens. In this analysis, failure is exclusively defined as switching regimen for toxicity, adverse effects, viral failure, clinical/immunological failure, lost to follow-up, and death. Patients with any previous antiretroviral treatment exposure before starting a first-line regimen in an AR program were also excluded from the modified ITT analysis. There were several patients who were alive and still on their first regimen at time of patient level outcome review, but a viral load sample was not obtained during review. These patients were also excluded from the modified intention to treat (modified ITT) analysis (Fig. 1).
To compare demographic and clinical characteristics among individuals initiating the different ART regimens in the review, we analyzed categorical variables using Pearson χ2 test and Wilcoxon rank-sum tests were used to compare continuous variables. Rates were calculated with 95% confidence intervals. Step-wise multiple regression analysis was then used to identify variables found to be associated with viral suppression. A 2-sided test with P value of less than 0.05 was deemed significant in comparisons. The statistical program used for analysis was Stata (StataCorp 2009. Stata Statistical Software: Release 11. College Station, TX: StataCorp LP).
In this review, an OT analysis of viral suppression outcomes of patients on first-line regimens containing EFV and TDF compared with the other recommended first-line combinations were analyzed. We also assessed the efficacy of EFV versus NVP regardless of nucleoside reverse transcriptase inhibitor backbone and compared TDF with AZT regimens regardless of nonnucleoside reverse transcriptase inhibitor (NNRTI) used.
From June 2004 to January 2009, 181,443 patients at AIDSRelief program sites in Kenya, Uganda, Nigeria, and Zambia were eligible to participate in the patient-level outcome review. By the end of December 2005, 17,180 patients had initiated ART; by end of 2006, 42,923 were on ART; by 2007, 83,478 were OT; by 2008, 126,195 total had started antiretroviral treatment; by end of 2009, 163,317 and by middle of 2010, 185, 486 cumulative patients were treated with ART. Between 2006 and 2010, 10,040 (5.5%) of these patients were randomly selected to have patient-level outcome review. At the time of cross-sectional analysis, 78.5% of the selected patients were alive, in care and still taking ART. A viral load sample was obtained from 5723 patients, representing 57% of all randomly selected patients. The mean age was 38 years, 66% were female and 13.1% had previously exposure to antiretroviral treatment. Less than 1% were documented to have received single-dose NVP, 7.55% had active TB diagnosed or where on TB therapy at time of ART initiation, and 14.3% of patients met criteria for poor adherence although on ART.
Of the 10,040 patients in the patient-level outcome review, 3862 adults initiated ART on 1 of 4 regimens of interest and were included for analysis. Of these, 1529 (39.6%) initiated AZT/3TC/NVP, 871 (22.5%) initiated AZT/3TC/EFV, 630 (16.3%) initiated TDF/XTC/NVP, and 832 (21.5%) initiated TDF/XTC/EFV (Fig. 1). The mean time OT was 15 months [interquartile range (IQR): 10–23]. Mean time varied according to the regimen: 14 months (IQR: 11–20) for AZT/3TC/NVP, 14 months (IQR: 11–20) for AZT/3TC/EFV, 21 months (IQR: 11–29) for TDF/XTC/NVP, and 16 months (IQR: 10–28) for TDF/XTC/EFV.
Among the 3862 patients included in the analysis, there were significant differences in baseline clinical and demographic characteristics by treatment groups. The proportion of means test compares characteristics of those on TDF/XTC/NVP, AZT/3TC/EFV, and AZT/3TC/NVP to patient on TDF/XTC/EFV. Patients who initiated TDF/XTC/EFV were more likely to be male, more likely to have baseline CD4 counts <100 cells per cubic millimeter and TB coinfection. Pregnant women were more likely to be started on AZT/3TC/NVP compared with TDF/XTC/EFV, and female patients were more likely to be treated with AZT/3TC/NVP and TDF/XTC/NVP. There was significantly higher adherence found in patients on TDF/XTC/EFV compared with the other regimens regardless of NNRTI used. There were no differences in previous ART exposure between regimens (Table 1).
Figure 2 shows the viral load suppression for the ITT, modified ITT, and OT analysis. The OT viral suppression analysis revealed that patients on TDF/XTC/EFV achieved higher rates of viral suppression when compared with patients on TDF/XTC/NVP, AZT/3TC/NVP. No significant differences were seen between AZT/3TC/NVP and TDF/XTC/NVP or between TDF/XTC/EFV and AZT/3TC/EFV. No significant differences were seen in the modified ITT or the ITT analysis among the 4 regimens.
In the ITT analysis, patients who switched for any reason were considered failures. Of those who started on AZT/3TC/NVP, 251 (16%) switched to an alternate regimen within an average of 7 months of treatment initiation (range: 6–9months), 191 (21%) patients who initiated AZT/3TC/EFV switched within an average of 6 months (range: 4–7), 159 (25%) patients who initiated TDF/XTC/NVP switched within an average of 10 months of treatment (range: 9–12), and 310 (37%) patients who started on TDF/XTC/EFV experienced a switch within an average of 13 months (range: 12–15). Supplemental Digital Content 1 (see Table 1, http://links.lww.com/QAI/A288) shows the reasons for antiretroviral switches. A majority of switches were documented as “other”. Although we were not able to specifically describe the “other” category, based on previous analyses, our assumption is that this category primarily represents undocumented toxicities ascribed to the antiretroviral switched. For EFV-based regimens, there was a programmatic change from EFV to NVP in 2007–2008 in our Uganda programs due to significant cost differences between NVP and EFV resulting in large-scale switch off TDF/XTC/EFV regimen onto TDF/XTC/NVP regimens. For the switches due to defined toxicity and adverse effects, we did not use AIDS Clinical Trials Group grading as a clinical tool. Treating clinicians were given access to alternative therapy to utilize when they deemed drug toxicity or drug intolerance was severe enough to merit a change of regimen.
The modified ITT analysis considered failures to be switches exclusively for toxicity, viral failure before patient-level outcome review, clinical failure, or adverse effects. These factors represented 4.9% of the total switches. Switches due to these more clinically relevant reason represented 19 (2.0%) on TDF/XTC/NVP, 89 (9.7%) on AZT/3TC/NVP, 50 (5.4%) on AZT/3TC/EFV, and 26 (2.8%) on TDF/XTC/EFV, representing overall a small percentage of the treatment failure.
In the unadjusted multivariable OT analysis where TDF/XTC/EFV was the reference category, patients on AZT/3TC/NVP (P < 0.001) and TDF/XTC/NVP (P < 0.001) were less likely to have a suppressed viral load compared with those on TDF/XTC/EFV. Patients on AZT/3TC/EFV (P < 0.161) were less likely to be suppressed compared with those on TDF/XTC/EFV although this relationship was not statistically significant. In the adjusted model, there were no differences in the odds ratio of achieving viral load suppression between the regimens. Baseline CD4 cell count less than 100 cells per cubic millimeter (P < 0.021) and age older than 30 (P < 0.004) were the most significant variables impacting viral load outcome for all regimens and had a greater impact on all other regimens compared with TDF/XTC/EFV (Table 2).
The OT suppression rate for EFV was 91.4% compared with 85.8% for NVP. The bivariate analysis comparing EFV-based to NVP-based regimens showed that patients on a NVP-based regimen were significantly less likely (P < 0.03) to suppress virus compared with those on an EFV-based regimen independent of the nucleoside. These results are similar to other investigators findings.21–27 (Table 3). In the bivariate analysis, we found a significant difference in viral suppression favoring TDF compared with AZT-based regimens with an odds ratio of 0.56 (P < 0.001), but this difference was not significant in the multivariable regression analysis (see Table, Supplemental Digital Content 2, http://links.lww.com/QAI/A289).
Our analysis provides additional information that the combination of TDF/XTC/EFV has outstanding efficacy in a difficult to treat population, with a 92% OT viral suppression <400 copies per milliliter and a modified ITT viral suppression rate of 82.4%. When comparing the other recommended first-line regimens in the same population, we found no significant difference in viral suppression in OT and modified ITT analyses in patients started and maintained on TDF/XTC/NVP compared with AZT/3TC/NVP and AZT/3TC/EFV after an average of 14 months OT. However, patients treated with TDF/XTC/EFV achieved significantly higher rates of viral suppression in the OT analysis when compared with the other regimens studied. The 92% OT viral suppression rate we observed with TDF/XTC/EFV is also consistent with published prospective clinical trials of EFV used in combination with TDF regardless of use with FTC or 3TC.30–32 A recent meta-analysis showed improved efficacy of TDF/FTC/NVP regimens compared with TDF/3TC/NVP regimens that could have had a possible impact on our observed efficacy of TDF/XTC/NVP, but we could not determine this in our analysis.16
Because this was a cohort study, patients were not randomly assigned to starting regimens. The wide range of provider experience in the use of ART exerts a strong influence on the choice of one-drug regimen over the other and on decisions of when to change drugs. Our program had a strong on-site technical assistance component and re-enforced clinical indications to which regimens to start, and provided baseline and follow-up laboratory tests. In addition, we made every effort to supply a wide array of first-line therapy for clinical indications. The modified ITT results were consistent across all regimens with very similar and expected change rates for toxicity of all regimens indicating good clinical practice as a whole. The bivariate analysis showed a strong treatment bias on which patients were treated with a NVP-based or EFV-based regimen. These biases clearly represent an “indication” bias in which NVP was preferentially used in women of child-bearing potential, and EFV was used in men and patients with possible TB. We saw no bias toward previous ART exposure and regimen used. It seems that more advanced patients were placed on TDF/XTC/EFV regimens possibly also reflecting a bias favoring the novel regimen for more advanced patients. Using our strict adherence criteria, we still observed a high overall adherence rate. However, there was a lower level of adherence seen with use of strictly twice daily (BID) regimens.
Baseline CD4 below 100 cells per cubic millimeter was the factor most strongly associated with a lack of viral suppression. Baseline CD4 was strongly associated with lack of suppression for all regimens, but patients on TDF/XTC/EFV had higher odds of viral suppression with a low baseline CD4 of <100 cells/mm3 compared to patients on other regimens. The overall higher rates of OT viral suppression outcomes of TDF/XTC/EFV compared with TDF/XTC/NVP were seen despite the strong treatment bias of using TDF/XTC/EFV combinations in patients with active TB and CD4 counts <100 cells per cubic millimeter. We also observed a greater effect of baseline CD4 <100 cells per cubic millimeter on the viral suppression rates among patients on NVP-based regimens compared with EFV-based regimens. This effect has been seen in other cohort studies and trials.27,33 Because a low CD4 may correlate with high viral loads, it is possible that these observations are indicative of the effect of a high baseline viral load on therapeutic efficacy and that a potency difference between EFV and NVP likely exists. Because presenting for care with advanced disease is common in resource-limited settings, the higher probability of treatment failure with NVP-based regimen in this population is of real concern and should be further explored.
This study is limited by its cohort cross-sectional design, and strong conclusions should be drawn with caution. However, the overall estimates of efficacy are within the range of other prospective clinical trial results in different populations, and the major conclusions we believe are robust. These findings lead one to consider whether EFV should be uniformly adopted as the first-line NNRTI of choice based on efficacy, ease of use, safety at all CD4 ranges, once-daily dosing profile, single pill fixed-dose generic combinations, safety data, and lack of clinically significant drug–drug interactions with rifampin. Although TDF/XTC/EFV show outstanding outcomes, the absolute teratogenicity risk of the use of EFV in women of child-bearing age needs to be determined before preferentially recommending this regimen for all patients. With the decreasing price differential between EFV and NVP, cost may no longer be a major factor in the choice between these 2 NNRTIs, and greater efficacy with EFV as shown should inform programmatic preference of EFV when compared with NVP in appropriate patients.
The authors acknowledge the local AIDSRelief hospitals and clinics providing antiretroviral care and treatment for more than 350,000 patients at the time this article was written. We also acknowledge the ministries of health in all AIDSRelief countries mentioned in this article.
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