Abstract
Introduction
The introduction of combined antiretroviral therapy (ART) has dramatically reduced the morbidity and mortality due to HIV infection. 1 –3 The potency of ART today is such that the risk of virologic failure has been greatly reduced with new combinations, 4,5 and even patients with multiresistant virus can achieve a full suppression of viral replication. 6 However, immune restoration needs a few months even when plasma viral load is suppressed, and this explains why late initiation of ART is associated with an increased risk of disease progression and death. 7 Also, low CD4 counts are associated with an increased risk of AIDS and non-AIDS-related cancers, suggesting that apart from the full control of viral replication, the goal 8 of HIV therapy should be to reach a CD4 count of 500 cells/mm3. Indeed, above this threshold, life expectancy of HIV-infected patients reaches that of non-HIV-infected individuals. 9 All recent guidelines for HIV therapy agree on the benefits of early initiation of ART to achieve these goals, and the need to expand HIV testing to reduce the proportion of late presenters who already have AIDS or a CD4 count below 200 cells/mm3 at the time of their first visit. 10 –12 Despite the large number of drugs and combinations available, few are recommended for treatment initiation based on their efficacy, short- and long-term tolerability and safety, convenience, and cost. All guidelines are also regularly updated to provide physicians with the more accurate information for improving the care of their HIV-infected patients. Few studies however are available to look at the adequacy of “real-life” care with these guidelines outside the setting of clinical trials or cohorts. 13 We wished therefore to review the characteristics and outcome of HIV-infected patients who started ART in our center and to asses the adequacy of our clinical practice with current national recommendations.
Materials and Methods
Study Design
We performed a retrospective study in the Infectious Diseases Department of the Saint Louis Hospital in Paris, a university hospital with a large HIV clinic, from January to December 2007. During this period, 19 physicians were in charge of 2484 HIV-infected patients.
We enrolled in this study all the HIV-infected adults who started their first ART in 2007, as long as ART was prescribed in our center. Patients who were not ART naive or received ART for postexposure prophylaxis, for prevention of maternal-to-fetal transmission of HIV were excluded. Data were collected from our computerized database (NADIS©) and validated with the patient charts. All patients gave informed written consent to have their data recorded in the computerized database and used for research purposes.
Two investigators collected the following data at baseline: demographic characteristics (age, sex, country of origin, and route of contamination), comorbidities (including cardiovascular and hepatitis B virus [HBV]/hepatitis C virus [HCV] coinfections), clinical status, time between first visit to our center and initiation of ART, CD4 count, and plasma HIV RNA levels. We also recorded the type of ART that was prescribed, and whether a genotypic-resistance test was performed before ART initiation. Time of ART initiation and choice of ART were then assessed for their adequacy to French guidelines. 12
We also wished to assess the 1-year clinical efficacy of ART in those patients and recorded AIDS events, deaths, and severe non-AIDS events (renal dialysis, liver failure, cancer, and coronary diseases) that occurred during the 12 months following ART initiation. We also recorded all hospitalizations during the same period and all changes in ART regimens. The CD4 counts and plasma viral load data were also collected, and we assessed the proportions of patients with plasma viral load <50 copies/mL and the cumulative proportion of patients with virologic failure defined as a viral load >400 copies/mL after at least 24 weeks of ART.
French Guidelines in 2007
Antiretroviral therapy should be started as early as possible for symptomatic patients, and for asymptomatic patients when the CD4 count was <350 cells/mm3 and before it dropped to <200 cells/mm3. Antiretroviral therapy was recommended for asymptomatic patients with CD4 counts >350 cells/mm3 in case of a high viral load (>100 000 copies/mL). Recommended ART combination included 2 nucleoside reverse transcriptase inhibitors (NRTIs) + 1 protease inhibitor boosted by ritonavir (PI/r) or 2 NRTIs + 1 nonnucleoside reverse transcriptase inhibitor (NNRTI). First-line combinations recommended were (abacavir [ABC] or tenofovir [TDF], or zidovudine [ZDV]) + (emtricitabine or lamivudine [3TC]) + (fos-amprenavir/r [FPV/r] or lopinavir/r [LPV/r] or saquinavir/r [SQV/r] or atazanavir/r [ATV/r]) or (ABC or didanosine [ddI] or TDF or ZDV) + (emtricitabine or 3TC) + EFV. The combination of 3 NRTIs (ZDV + 3TC + ABC) was recommended only if the viral load was <100 000 copies/mL and PIs or NNRTIs could not be used.
Statistical Analysis
Quantitative variables were presented as median, first, and third interquartile ranges (IQRs). One-year outcome variables were analyzed using intent-to-treat analysis with observed data for CD4 counts and missing data counted as values above 50 copies/mL for viral load assessments. An intent-to-treat analysis with observed data was also performed to assess the proportion of patients with plasma HIV RNA levels less than 50 copies/mL at 1 year. Data from patients lost to follow-up were censored at their last visit. A number of risk factors for virologic failure were assessed: age, sex, US Centers for Disease Control and Prevention (CDC) stage, baseline CD4 and viral load, ART regimen, once a day versus twice a day regimens, lack of adherence (defined as nonadherence recorded at least once by the physician in the patient’s chart) using Fisher exact tests, with Stata version 8.2 software.
Results
Patients Baseline Characteristics
Among 195 patients identified in our database, 77 patients were excluded from the study (initiation of ART in another center, n = 69; ART for postexposure prophylaxis, n = 7; and ART for prevention of mother-to-child transmission of HIV, n = 1) and 118 met the inclusion criteria and were further analyzed. Most patients were male (n = 96, 81%), 53 (45%) were men who have sex with men (MSM), 52 (44%) were heterosexuals, and very few were intravenous (IV) drug users. Most patients originated from Europe (38%) or sub-Saharan Africa (39%). All patients were infected by HIV-1, except 3 patients who had HIV-2 infection. Only a few patients presented with comorbidities at baseline, and most patients (80%) were asymptomatic. Fifty patients (42%) however were late presenters with either a CD4 count <200 cells/mm3 or AIDS. Interestingly, the time between HIV diagnosis and ART initiation was quite long, with a median of 19 months with a wide IQR: 2 to 54 months, but the time between the first visit to our clinic and ART initiation was shorter, with a median of 3 months. Median CD4 count was 242 cells/mm3 (IQR range: 156; 295), and median plasma viral load was 4.87 log10 copies/mL (IQR: 4.33; 5.34) at the beginning of ART (Table 1).
Baseline Characteristics of 118 Patients Starting Antiretroviral Therapy in 2007
Abbreviations: ART, antiretroviral therapy; CDC, US Centers for Disease Control and Prevention; ddI, didanosine; d4T, stavudine; IV, intravenous; IQR, interquartile ranges; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; ZDV, zidovudine.
Adherence to 2006 French Guidelines
Time of ART initiation
Antiretroviral therapy was initiated in 12 patients with a CD4 count >350 cells/mm3, 5 of whom were symptomatic (including 1 with tuberculosis) and 2 of whom had a plasma viral load >100 000 copies/mL. Treatment initiation was therefore not in adequacy with guidelines in the 5 remaining patients. In 44 other patients, ART was started too late since the patients had a CD4 count <200 cells/mm3. Of these 44 patients, 29 had a recent (<3 months) diagnosis of HIV infection, 2 refused earlier initiation of ART, and 13 missed scheduled visits. Five other patients had AIDS with CD4 counts between 200 and 350 cells/mm3. Overall, only 64 patients (54.2%) received ART in accordance with the current guidelines
Choice of ART
The vast majority of patients (114 of 118 [97%]) received a combination of ART that was in agreement with the guidelines. Indeed, 62 (52%) patients received a combination of EFV + 2 NRTIs and 47 patients (40%) a combination of a boosted PI + 2 NRTIs. Five other patients were also considered to be treated according to recommendations (1 patient with a low plasma viral load and contraindication to PIs and EFV received a triple NRTI combination, and 3 patients were enrolled in a clinical trial and received enfuvirtide in addition to a standard regimen and were also considered as being treated according to the guidelines). The 4 patients who received a nonrecommended regimen for various reasons (severe depression, psychiatric disease, and renal dialysis) achieved a full suppression of viral replication under ART during follow-up (Table 1).
Among NNRTIs, only EFV was used for initial ART in 65 (55.1%) patients, 3TC or emtricitabine were used in all but 1 patient (99%), and TDF in 91 patients (77.1%). Lopinavir/r (19.5%) and ATV/r (16%) were the most frequently used boosted PIs.
The most frequently prescribed ART for initial therapy in our center in 2007 was a combination of EFV, TDF, and emtricitabine, given to 56 patients (48%). Most patients (70%) also received a once-daily (QD) regimen.
Baseline resistance genotype
Although required by national recommendations a baseline resistance genotype was performed in only 66 patients overall (58%), and in 39 (60%) of the 65 patients who received an EFV -based regimen. In all, 2 patients had resistance mutations at baseline: 1 NRTI-associated mutation (69D) in one patient, and a combination of PI-associated mutations in the second patient (M46L + I84A associated with L10F + G16E + L33F + I54V + Q58E + D60E + I84A)
Outcome at 1 Year
At 1 year, 16 (13.5%) patients were lost to follow-up. The median follow-up of these 16 patients was 3.5 months (2, 7), and their baseline characteristics were similar to those of the other patients (data not shown). Among these 16 patients, 6 eventually came back to our center but outside the 1-year period of the study, and 4 moved to another center.
Therefore, data regarding outcome are available for only 102 patients, 98 of whom had CD4 and viral load data available at 1 year.
As shown in Table 2, only 5 patients (4.9%) progressed to AIDS (recurrent cytomegalo virus [CMV] retinitis, anal lymphoma, and cervical cancer), severe non-AIDS (breast cancer) events, or death (epidermoid anal carcinoma already present at baseline) during follow-up. On the other hand, 19 patients (18.6%) were hospitalized during the study period, mainly because of non-AIDS-defining infections or psychiatric disorders. Also, 2 patients with tuberculosis developed immune reconstitution syndromes that required hospitalization.
One-Year Outcome Following Initiation of Antiretroviral Therapy
Abbreviations: ITT, intention to treat; IQR, interquartile ranges.
aNumber of events compared to the number of patients receiving the drug.
bHLA B5701 negative.
During the follow-up, ART was changed in 21 patients (21%), mainly for drug-related adverse events. Efavirenz-related adverse events led to ART changes in 11 (17%) of 65 patients who received this drug for initial ART. Only 2 (2.2%) of the 91 patients receiving TDF had to discontinue this drug because of increases in plasma creatinine levels.
The proportion of patients reaching a plasma HIV RNA level <50 copies/mL at 1 year was 82 (69.5%) of 118 in an intent-to-treat, missing equals failure analysis, and 82 (84%) of 98 using observed data. The median increase in CD4 count from baseline to 1 year was 178 cells/mm3 (83, 278), with a median CD4 count of 389 cells/mm3 (30, 538). Cumulative rate of virologic failure was 10 (10.2%) of 98 patients at 1 year. All 10 patients with virologic failure had a resistance genotype performed: in only 1 patient, drug-resistance mutations associated with EFV, TDF, and emtricitabine resistance emerged (K65R + M184V + K103N).
When assessing variables associated with virologic failure (Table 3), only age, the reported lack of adherence, and a high baseline viral load above 100 000 copies/mL were both significantly associated with virologic failure.
Risk Factors for Virologic Failure a
Abbreviations: CDC, US Centers for Disease Control and Prevention; IQR, interquartile ranges; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI/r, protease inhibitor boosted by ritonavir.
aDefined as a Plasma Viral Load >400 copies/mL.
bData not available for 2 patients in the virologic success group and 1 in the virologic failure group.
Discussion
Assessment of professional practices are useful to improve medical care. In this retrospective study of 118 patients starting ART in 2007 in a French hospital, we show that ART prescriptions were conformed to national recommendations with regard to the choice of the regimen but not to the time at which ART was initiated.
Indeed, time of ART initiation was in agreement with national guidelines in only 64 (54.2%) patients, mainly because ART was started too late in many patients. In all, 50 patients (42%) started ART with AIDS or a CD4 count <200 cells/mm3 and although the majority of these patients were late presenters, some patients refused earlier initiation of ART and others missed scheduled appointments. Very few patients started ART earlier than 2006 French recommendations, and although these patients would be considered as being treated in agreement with the updated 2010 guidelines, 14 this would not have affected the overall findings of this study.
Although late initiation of ART has been associated with an increased risk of HIV disease progression and death, 7 this finding of delayed ART in antiretroviral-naive HIV-infected patients is common in recent audits in Europe. 15,16 We should therefore address this issue of HIV-infected patients who present late to care by promoting the widespread use of HIV testing especially in high-risk groups. Indeed, in our study 45% of patients were MSM and 39% came from sub-Saharan Africa, a highly endemic region for HIV. A recent national campaign has been launched in France to promote HIV testing in the general population and in high-risk groups (plan SIDA 2010-14: http://www.sante.gouv.fr/IMG/pdf/DP_campagne_lutte_Sida_2010.pdf). General practitioners are also encouraged to propose HIV tests to their patients, and specifically to those who were never tested or who belong to high-risk groups.
A significant proportion of patients in our study also deferred ART initiation because they missed appointments with their physicians. Attempts should be made in HIV care centers such as ours to better identify these patients and the reasons explaining their behavior. We should find ways to have these individuals come back to see their HIV physicians, with the help of their general practitioners and of community groups.
On the other hand, our study showed that ART combinations used for treatment initiation were in agreement with the national guidelines in most cases. Indeed, 97% of ART prescriptions used recommended combinations of antiretroviral drugs, which is similar to other studies. 15,17,18 This result is satisfactory since the use of nonrecommended ART has been associated with a higher incidence of ART switch and worse immunologic and virologic outcomes. 13
However, in our study, resistance genotypic tests were performed for only 66 (58%) patients before treatment initiation, and this proportion was similar whether or not patients started a PI or an NNRTI-based regimen. This relatively poor outcome is likely due to the fact that this recommendation appeared for the first time in 2006 guidelines and was not yet implemented by all physicians, despite the availability of genotypic-resistance tests in all HIV clinics in France. Of note, among patients who had a baseline genotypic-resistance tests, the prevalence of resistance mutation was low (2 of 68, 3%), and similar to the prevalence of HIV resistance in primary infection cohorts in France. 19 This issue of resistance testing before starting ART is particularly critical when an NNRTI-based regimen is used since the presence of NNRTI-resistance mutations is clearly associated with treatment failure. 20 These results were discussed with the doctors in our department and future studies should assess whether this recommendation is now implemented.
Our study also confirmed the potency of today’s ART. Despite a low-median CD4 count at the beginning of ART in our patients, only 1 of the 118 patients died of an anal cancer already present at baseline, and very few developed AIDS-defining events or severe non-AIDS events. It is interesting to note however that 4 of these 5 events were cancers, an emerging concern in patients with HIV infection today, especially in those with low CD4 counts. 8 Indeed, although the CD4 count increase at 1 year in our patients was significant and similar to other studies in naive patients, more than half of the patients did not reach a CD4 count of 500 cells/mm3 or more, a threshold above which the risk of cancer is significantly reduced. 8 Of note, 19 (18.6%) patients required hospitalization during the study period mainly for infectious diseases or psychiatric disorders, underlining that HIV-infected patients remain at risk of these diseases that should be better prevented and addressed.
The virologic efficacy of ART in our study was similar to that of clinical trials, with 69.5% of patients reaching plasma HIV RNA levels below 50 copies/mL at 1 year in an intent-to-treat, missing equals failure analysis and 84% using observed data. Part of these results can be explained by the pretty high rate (13.5%) of patients lost to follow-up with no data available, and efforts should be made to maintain these patients under care. We were not able, however, to identify risk factors associated with loss to follow-up at baseline, probably because of the small size of our study. Indeed, in another much larger French cohort, a number of risk factors for loss to follow-up were identified such as young age <30 years, IV drug use, no phone number provided, no primary care physician, and a sub-Saharan Africa origin. 21
The cumulative rate of virologic failure in this cohort was 10.2% at 1 year, and although fewer failures were seen among patients receiving a QD regimen or an NNRTI-based regimen, only a high baseline viral load and a reported lack of adherence to the ART regimen were significantly associated with failure. This is in agreement with several studies reporting a strong correlation between the lack of adherence and ART failure. 22,23 The role of adherence is further supported by the low rate of resistance mutation among patients with virologic failure since resistance to ART was detected in only 1 patient. These data again underline the role of patients education to promote adherence to ART.
Our study also provided information regarding the tolerability of a first ART. At 1 year ART was changed in 21% of our patients, mainly for drug-related adverse events (15.6%). These proportions are similar to those reported in other cohorts. 24,25 Efavirenz-related adverse events were the major reason for ART change in our cohort with 17% of all EFV-treated patients discontinuing this drug within 1 year. This is different from data reported in clinical trials and previous cohorts in which these proportions were much lower. 26,27 These results could be explained both by the high proportion (55.1%) of patients who received EFV-based ART in our study and by real-life management of EFV-related central nervous system symptoms and rash according to the many other treatment options available.
In conclusion, our study showed that ART prescriptions were in agreement to the national guidelines in terms of the regimen used, but many patients were treated too late, a resistance genotype was not performed before ART initiation in all patients, and the proportion of patients nonadherent to their regimen or lost to follow-up remained high. These are areas for improvement that should lead to better virologic and clinical outcomes in future assessments of our practices.
VL and MAB contributed equally to this work. This study was presented at the 12th European AIDS Clinical Society Meeting, Cologne, Germany, November 12 and 13, 2009, abstract No PE18.5/4.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
The author(s) received no financial support for the research, authorship, and/or publication of this article.