After the introduction of highly active antiretroviral therapy (HAART), the mortality and morbidity of HIV infection decreased dramatically, to the extent that it is now a chronic disease.1 HAART has some disadvantages, however, such as severe adverse effects, resistance to drugs, and its high cost. Furthermore, current regimens cannot eradicate infection, with the result that therapy is for life. Therefore, it is essential to define the determinants of progression to know exactly when to start therapy.
The most important factor affecting the prognosis of HIV infection is the CD4 cell count before starting therapy. Currently, one of the main controversies over when to initiate HAART concerns HIV-infected patients with an intermediate immunologic level (CD4 count of 200 to 350 cells/μL). Most studies have found a worse prognosis, with a higher risk of death or progression to AIDS, in patients who started HAART with a CD4 count <200 cells/μL compared with those who started with high CD4 cell levels.2-8 In those patients who started HAART with 200 to 350 cells/μL, however, studies differ in their results. Although some observational studies have found a higher risk of progression to AIDS or death,6,9 others have not found significant differences.2,3,8 In addition, some studies have found a different risk of disease progression depending on viral load (VL)10 or on whether an undetectable VL was reached.11 These authors recommend taking VL into account when deciding the optimal time to start treatment.
A major limitation of some of the reported differences is the lack of an adjustment for lead time, which results in biased risk estimates. Briefly, in an ideal hypothetic clinical trial designed to establish when to initiate HAART, HIV-positive AIDS-free patients would be randomly assigned to start or defer treatment and would be followed up from randomization to AIDS. Thus, to mimic such a trial using data from observational studies, previous survival time for individuals who started treatment at low immunologic levels (lead time) and previous events in those who initiate therapy later (the unseen fast progressors) should be taken into account so that a common origin for the time-to-event analysis can be determined.3,9,12,13
Since 1998, we have been conducting an observational study that includes HIV-infected patients from 9 hospitals within Catalonia and 1 from the Balearic Islands (PISCIS Cohort Study). Until December 2004, the study included 6922 patients with 17,766 person-years of follow-up. The PISCIS Cohort has provided us with information on clinical epidemiologic trends in the initial diagnosis of HIV and on the appropriate use of antiretroviral treatment.14
The aims of this study are to determine factors related to progression to AIDS or death in HIV-infected patients from the PISCIS Cohort Study and to assess the optimal time to initiate HAART on time to AIDS using methods that take lead time into account.
PISCIS Cohort Study
The PISCIS Cohort Study was started in 1996 with the development of an informatics application to computerize the clinical records of HIV-infected patients. In 2000, after a feasibility study, information from the routine clinical follow-up of all newly attended patients (≥16 years of age) was retrospectively collected from 1998 to 2000, and prospectively thereafter. Detailed methods for the cohort have been described elsewhere.14
Quality was assessed by means of quality-control reports and quality-control visits for each center. To reduce the lack of information on patients lost to follow-up, hospitals periodically matched the data with other sources of information within the hospital (clinical records and other computerized records of death or hospital admissions from centers). Only a few centers performed active follow-up by telephone or mail when patients did not keep their appointment. The overall loss to follow-up of the PISCIS Cohort is 26%, and it is 18% for naive patients who started HAART.
Confidentiality was ensured through nonpersonal identification. The study was approved by the ethics committees of the participating hospitals.
CD4 T lymphocytes were quantified by flow cytometry. HIV-1 RNA levels were quantified by reverse transcriptase (RT) polymerase chain reaction (PCR), branched DNA, or nucleic acid sequence-based amplification (NASBA) techniques.
We included treatment-naive HIV-infected patients who initiated HAART between January 1998 and June 2004, were AIDS-free before the treatment started, and were on HAART for at least 1 month.
HAART was defined as the combination of at least 3 antiretroviral drugs, according to Spanish15 and international16 guidelines. This analysis included the following regimens: 1 or 2 protease inhibitors (PIs) with 2 nucleoside reverse transcriptase inhibitors (NRTIs), 1 nonnucleoside reverse transcriptase inhibitor (NNRTI) with 2 NRTIs, 3 NRTIs, or other combinations. AIDS-defining illnesses are based on the 1993 Centers for Disease Control and Prevention clinical case definition17 without considering a CD4 count <200 cells/μL as AIDS defining. All causes of mortality were considered. Patients were assigned to 1 of 3 groups based on their CD4 cell count at baseline, defined as the nearest CD4 cell determination before initiating HAART within a 6-month period (>350, 200 to 350, and <200 cells/μL). In addition, we considered VL at baseline as the nearest determination before initiating HAART within a 6-month period and assigned patients depending on whether they had a high VL (HIV-1 RNA ≥100,000 copies/mL) or low VL (HIV-1 RNA <100,000 copies/mL). Hepatitis B virus (HBV) and hepatitis C virus (HCV) were defined as the presence, before initiating HAART, of hepatitis B surface antigen (HBsAg) and HCV antibody, respectively. The period of initiation of HAART was categorized according to the availability of therapy: January 1998 through December 2000 (early HAART) or January 2001 through June 2004 (midterm HAART).
For the descriptive analysis, quantitative characteristics were described using median values and interquartile ranges (IQRs) and qualitative characteristics using percentages. The Kruskal-Wallis test and Pearson χ2 test were used to compare the characteristics of the baseline CD4 cell count groups. Cumulative progression probabilities to AIDS/death were computed using the Kaplan-Meier estimator.
Cox proportional hazards models were used to assess the determinants of progression to AIDS or death after the initiation of HAART. The hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were calculated. Multivariate models were adjusted by calendar period of treatment (early and midterm HAART), which was treated as a time-dependent variable. Potential confounding factors and variables with a significant unadjusted HR at the 0.20 level were included in the initial multivariate model. The best multivariate model was obtained by systematically comparing the deviance of the models. Patients included in the analysis not seen in the year preceding the censoring date were censored alive at the date of their last visit. Patients in active follow-up were administratively censored on December 31, 2004.
To estimate the impact of deferring the initiation of HAART on the progression of HIV infection to AIDS, we applied methodologies designed to mimic hypothetic randomized experiments as closely as possible.13 Briefly, when time to AIDS for patients who initiated HAART with a high CD4 count (eg, >350 cells/μL) was compared with that for patients who deferred HAART to lower levels (eg, 200 to 350 cells/μL), a common time-to-event analysis was performed by adding to the deferred group previous survival time (lead time) to progress from the early stage to the late stage, when therapy was initiated. Moreover, the survival time of patients who progressed to AIDS from a high CD4 cell count before reaching lower levels (unseen fast progressors) was added to the analysis. The procedure was performed analogously when those who initiated HAART at a CD4 count of 200 to 350 cells/μL were compared with those who deferred HAART until they reached a CD4 count <200 cells/μL.
Lead time for patients who transitioned to lower CD4 T-cell levels when HAART was initiated and lead time for the fast progressors were generated using the parametric cumulative models of progression reported by the Multicenter AIDS Cohort Study (MACS) with data from the pre-HAART era (Fig. 1),13 by taking advantage of the idea that therapies before December 1995 did not substantially alter the course of the disease. More specifically, we generated lead times to progress from a CD4 count >350 cells/μL to 200 to 350 cells/μL and from 200 to 350 cells/μL to <200 cells/μL, without AIDS, from the estimated log-normal cumulative probability distributions presented in Figure 1 (thick solid lines show cumulative incidence estimates of the time to the CD4 transition without AIDS). Additionally, fitted models for the number of fast progressors (unseen sample) and their survival times were used: the estimated proportion of fast progressors was 0.03 in the group with >350 cells/μL and 0.12 in the group with 200 to 350 cells/μL. Similarly, lead times to progression to AIDS from >350 cells/μL and 200 to 350 cells/μL without reaching a lower CD4 cell threshold were estimated using the log-normal cumulative probability distributions presented in Figure 1 (dashed lines show cumulative incidence estimates of the time to AIDS without CD4 cell transition).
Finally, the lead time and the unseen sample were multiply imputed (repeated 50 times), and the lead-time-adjusted HRs, which approximated the HRs obtained from a randomized deferral trial, were computed by combining the imputed survival times using multiple imputation techniques.18
The analyses were performed by intention to treat, ignoring treatment changes and interruptions.
A total of 3427 treatment-naive participants started HAART between January 1, 1998 and June 30, 2004. Of these, 2520 (73.53%) were AIDS-free before starting HAART, 2129 (84.48%) had had an available CD4 T-cell count within 6 months before initiating HAART, and 2035 (95.58%) were on HAART for at least 30 days.
The clinical and epidemiologic characteristics of the study population by baseline CD4 cell count groups are shown in Table 1. Of the 2035 patients included, 760 were in the group with <200 cells/μL at baseline, 650 were in the group with 200 to 350 cells/μL, and 625 were in the group with >350 cells/μL. The median age of the patients was 35.5 years, and 75.4% were men.
Determinants of HIV Disease Progression or Death
A total of 148 patients (7.3%) progressed to AIDS or death after a median follow-up of 34.3 months. Univariate and multivariate Cox models for risk progression are shown in Table 2. We found a higher risk for the group with a CD4 count <200 cells/μL (HR = 4.22, 95% CI: 2.63 to 6.78) than for the group with a CD4 count >350 cells/μL. We also found a higher risk of disease progression in older patients, men, injection drug users (IDUs), patients with HCV at baseline, those who initiated treatment with a PI-containing HAART regimen, and those with a high VL. In those patients who initiated HAART between January 2001 and June 2004, the risk was reduced by half. In the multivariate analysis, after adjusting by the effect of the calendar period, only a CD4 count <200 cells/μL, a high VL before starting HAART, HCV at baseline, and early HAART period remained significant.
A hypothesis on the linear trend in the risk of progression to AIDS or death according to the different levels of CD4 cell counts and VLs at HAART initiation was assessed using a combined variable (Fig. 2). We observed a higher risk of progression to AIDS or death in patients with a CD4 count <200 cells/μL and high and low VLs (HRs = 5.88 and 3.39, respectively).
When to Initiate HAART
In an unadjusted Cox regression analysis, we found a higher risk among patients who deferred treatment with <200 cells/μL (HR = 2.81, 95% CI: 1.79 to 4.40) than among those starting treatment with 200 to 350 cells/μL. Moreover, a higher risk of progression was found among those patients who deferred HAART until they had 200 to 350 cells/μL compared with those who started with >350 cells/μL, although this was not statistically significant (HR = 1.56, 95% CI: 0.84 to 2.90). When methodologies taking lead time into account were applied, the risk of progression to AIDS was higher for patients who initiated treatment with <200 cells/μL (HR = 2.97, 95% CI: 1.91 to 4.63) and for those who initiated treatment with 200 to 350 cells/μL (HR = 1.85, 95% CI: 1.03 to 3.33), compared with those who started treatment with 200 to 350 cells/μL and >350 cells/μL, respectively (Fig. 3).
The PISCIS Cohort is an observational prospective study that includes 70% of all new HIV infections reported in Catalonia and the Balearic Islands. We assessed the progression of HIV infection in 2035 asymptomatic naive patients on HAART with a median follow-up of 34 months. We found a higher risk of progression to AIDS or death in those patients who started HAART with a CD4 count <200 cells/μL. In addition, VL, HCV coinfection, and period of initiation of HAART were independent risk factors. After accounting for lead time and unseen events, a statistically significant risk of progression to AIDS was found in patients who delayed HAART initiation until they had a CD4 count of 200 to 350 cells/μL compared with those who initiated therapy with more than 350 cells/μL.
Determinants of HIV Disease Progression or Death
We observed a higher risk of progression to AIDS or death in patients who started HAART with <200 cells/μL, and this agrees with previous findings.2-9 Recently, some authors19 have found that the CD4 percentage (CD4%) could be important when deciding on the optimal time to start therapy, particularly in patients with a CD4 count of 200 to 350 cells/μL. In our study, however, the relative hazards of progression to AIDS or death for each CD4 cell count group were unaffected by adjustment for the CD4% (data not shown).
VL is also an important factor affecting the progression of HIV infection. In the MACS, Mellors et al20 estimated a different risk of long-term progression to AIDS according to a combination of CD4 cell count and VL groups. The Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) Collaboration21 analyzed 3226 patients to determine short-term risk at 6 months of progression to AIDS according to CD4 cell count and VL and the risk increased with higher VL for a given CD4 cell count. As in other studies,7,20-22 we observed an increased risk of progression in each CD4 cell count group with a higher VL (see Fig. 2). In addition, an independent effect of VL on progression to AIDS or death was also found after adjusting for other covariates, including CD4 cell count.
Moreover, we found a higher risk of progression to AIDS or death with increased age. This agrees with other observational studies, which found an increased probability of progression in older subjects with the same CD4 cell count and VL.7,21 There are no established gender differences in response to HAART, although some studies reported lower progression to AIDS and death in women.23,24 We found a greater risk of progression in men, although this did not reach statistical significance in the multivariate analysis.
Although it is well known that patients with HIV-HCV coinfection have increased morbidity and mortality,25,26 the question of whether HCV infection affects progression of HIV infection is more controversial. Some authors did not find a higher risk of mortality or AIDS-defining events,27,28 whereas others did find a higher risk of disease progression to AIDS or death in naive patients on HAART,29,30 in specific HCV genotypes,31 or in coinfected patients during the HAART era.32 Interestingly, we found a higher risk (HR = 2.40, 95% CI: 1.65 to 3.49) of disease progression to AIDS or death in HCV-positive patients. Our study had 642 HCV-positive patients from a total of 2035 HIV-infected patients. To our knowledge, the PISCIS Cohort Study is one of the largest studies (also see the article by De Luca et al29) to assess the influence of HCV on the progression of HIV infection. The risk of progression remains even if we account for other variables in the multivariate analysis, including IDU transmission group. A possible interaction effect between both variables was assessed performing separate analyses for the IDU and non-IDU groups, and we found that coinfection by HCV was an independent risk factor for progression to AIDS or death, even among the non-IDU group (data not shown).
Other treatment-related factors, such as HAART regimen or period in which HAART was initiated, could influence prognosis. Although we found a lower risk of progression to AIDS or death in patients who initiated treatment with NNRTI combinations in the univariate analysis, the association disappeared after adjusting for other factors. Conversely, we did find an important association between the risk of progression and the period of HAART initiation. Those patients who initiated treatment between January 2001 and June 2004 had half the risk of progressing to AIDS or death. These results are in accordance with recent studies that have found an increase in survival in HIV-infected patients during the period from 2000 to 200533 and a lower risk for development of AIDS over calendar years.34 Several factors, such as greater efficacy of new antiretroviral drugs, together with simplified dosing and less drug toxicity, which increases adherence, could lead to increased survival in HIV-infected patients treated during the late period.
When to Initiate HAART
In the absence of a randomized clinical trial to answer the question about when to initiate HAART, unadjusted HRs obtained from observational data are biased because of (1) confounding factors associated with early initiation of AIDS and (2) an inappropriate origin for the time scale. In our study, more accurate results for the relative hazards of disease progression were obtained after adjusting the survival curve by adding the lead time and including the unseen events (fast progressors). We found an HR of progression to AIDS of 2.97 in patients who deferred treatment with <200 cells/μL compared with those starting with 200 to 350 cells/μL. A more important finding was that the higher HR of progression to AIDS among patients who delayed initiating HAART until they reached 200 to 350 cells/μL achieved statistical significance compared with those who initiated therapy at >350 cells/μL. In view of these results, and if they could be confirmed by further collaborative studies, it would be advisable to revise the current guidelines that recommend not starting HAART with a CD4 count >350 cells/μL.
Our study has several limitations. First, this is an intention-to-treat study and we do not take into account adherence to treatment. Because this is a limitation for all 3 CD4 cell count strata, however, we do not expect there to be differences in adherence between groups. In addition, other factors related to lower adherence (eg, IDU transmission group, gender, age) were included in the multivariate analysis.
Second, estimations of the lead time were based on data from the MACS on AIDS-free HIV-infected individuals who were followed up during the pre-HAART period. Because our main assumption was that, up to December 1995, therapies did not considerably change the course of the natural history of HIV infection, in the absence of data such as those of the PISCIS Cohort, the use of external estimates was justified. Moreover, estimates of the probability of CD4 cell count transition reported by the MACS were based on patients with <500 cells/μL. Nevertheless, in our study, the lead-time-adjusted HR of patients with 200 to 350 cells/μL was obtained, thus allowing patients with >350 cells/μL to be included in the comparison.
Third, if external data from the pre-HAART period were available, more accurate estimates of progression might be obtained from CD4 cell count transition models according to combinations of different biomarkers (eg, CD4 cell count, VL) and other clinical endpoints (eg, death).
Finally, although clinical trials are the “gold standard” for assessing treatment efficacy, observational studies have provided valuable estimates of treatment effects in the general population using appropriate statistical methodologies.35-37 In this context, we could consider alternative methods that adjust appropriately for time-dependent confounders allowing causal inferences from prevalent cohort data.37,38 Given that these methodologies need a sufficient sample size to obtain stable estimates, however, it would be necessary to pool different cohorts to improve the analysis with regard to the question of when to initiate HAART.
In conclusion, this study shows that, apart from a low CD4 T-cell count and high VL, HCV coinfection is an important determinant of higher HIV disease progression or death, whereas the midterm HAART period was associated with higher survival. Our results reinforce the appropriateness of initiating HAART earlier in asymptomatic HIV-infected patients. Lead-time analysis suggested that the optimal time to start HAART is before the CD4 T-cell count falls to lower than 350 cells/μL. These results provide valuable information for clinical decisions about when to start HAART, particularly now that we have better antiretroviral drugs and more comfortable regimens.
The authors are indebted to Thomas O'Boyle for his assistance with the English version of the manuscript. They are grateful to D. A. Muñoz and S. Cole for their helpful comments and suggestions on the lead-time analysis. They are also grateful to all their patients and the health care providers involved in the PISCIS Cohort.
A. Jaén and A. Esteve conceived the study and wrote the first draft of the report. All authors contributed to the final draft. A. Esteve and A. Montoliu performed the statistical analyses with assistance and data interpretation from A. Jaén. J. M. Miró contributed to data interpretation. J. Casabona conceived the PISCIS Cohort. J. Casabona and A. Jaén were responsible for the scientific and technical coordination of the PISCIS Cohort.
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PISCIS Study Group
Steering Committee: J. Casabona, A. Esteve, A. Jaén, and M. Granell from the Centre d'Estudis Epidemiològics sobre ITS/VIH/SIDA de Catalunya, Badalona, Spain (CEEISCAT); J. M. Gatell and J. M. Miró from Hospital Clínic, Barcelona; J. Murillas and S. Riera from Hospital Son Dureta, Palma de Mallorca; D. Podzamcer and E. Ferrer from Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona; B. Clotet and C. Tural from Hospital Universitari Germans Trias i Pujol, Badalona; F. Segura and G. Navarro from Hospital Parc Taulí, Sabadell; L. Force from Hospital Mataró, Barcelona; J. Vilaró from Hospital General Vic, Vic; A. Masabeu from Hospital Palamós, Girona; I. García from Hospital Creu Roja, Hospitalet de Llobregat, Barcelona; and J. Altés from Hospital Alt Penedès, Vilafranca, Barcelona.
Data Manager and Computer Support: E. Puchol, Y. Alvaro, and A. Montoliu (CEEISCAT, Badalona); and Modesto Sánchez (Hospital Clínic-IDIBAPS, Universitat de Barcelona, Barcelona)
Clinical Staff: L. Zamora, F. Aguero, O. Sued, J. L. Blanco, F. García-Alcaide, E. Martínez, and J. Mallolas (Hospital Clínic-IDIBAPS, Universitat de Barcelona, Barcelona); G. Sirera, J. Romeu, A. Bonjoch, A. Jou, A. Ballesteros, E. Negredo, D. Fuster, and J. C. Martínez (Hospital Universitari Germans Trias i Pujol, Universitat Autónoma de Barcelona, Badalona); M. Santin, M. J. Barbera, M. Olmo, P. Robres, F. Bolao, J. Carratala, C. Cabellos, and C. Peña (Hospital de Bellvitge-IDIBELL, Universitat de Barcelona, Hospitalet de Llobregat, Barcelona); P. Barrufet (Hospital de Mataró, Barcelona); M. Guadarrama (Hospital Alt Penedès, Vilafranca, Barcelona); and M. J. Amengual, M. Sala, M. Cervantes, and E. Penelo (Corporació Sanitària Parc Taulí, Sabadell)