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ARTICLE

Predictors of a viral response and subsequent virological treatment failure in patients with HIV starting a protease inhibitor

Mocroft, Amanda1,4; Gill, M John2,3; Davidson, William2; Phillips, Andrew N.1

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Abstract

Introduction

The measurement of the plasma HIV RNA level, or viral load, in patients with HIV is becoming increasingly used to determine both prognosis and the effects of treatment; high levels of viral load have been shown to be associated with faster disease progression and with the emergence of drug-resistant viral strains [1–5]. The ultimate goal of treatment has now become to reduce the levels of replicating virus to an undetectable level (as determined using a highly sensitive assay), most often using a combination of potent antiretroviral drugs, including protease inhibitors. Recently published guidelines regarding the use of antiretroviral therapy now include the recommendation that both viral load and CD4 lymphocyte counts should be monitored regularly, and that plasma viral load should be reduced by as much and for as long as possible [6,7].

Protease inhibitors, such as saquinavir, ritonavir and indinavir, have been shown to have potent activity against HIV, and were introduced into clinical practice in 1996, after which their use has rapidly expanded. They may reduce the viral load to below the level of detection in a large proportion of patients, increase the CD4 lymphocyte count, and also reduce the incidence of death, new AIDS-defining illnesses and hospitalizations [8–15].

Factors related to the probability of viral load becoming undetectable include the choice of treatment regimen, initial viral load and previous antiretroviral treatments used by the patient (S. Staszewski, personal communication, 1998) [16–19]. Less clear, however, are the factors related to the re-emergence of detectable viral load. The aim of this study was therefore to investigate the factors related to a patient's viral load becoming undetectable during the first 6 months of treatment with a protease inhibitor among patients from Southern Alberta who started a protease inhibitor for the first time. In addition, amongst those patients whose viral load became undetectable, factors related to the subsequent re-emergence of detectable virus were also investigated.

Patients and methods

In October 1989, the Southern Alberta HIV clinic and its satellite clinics were mandated to provide exclusive access to both provincially funded antiretroviral drugs and also the laboratory monitoring tests used in HIV care. A total of 1500 patients had received care in the clinic at some time. Treatment was provided through 10 physicians who used national/international guidelines for treatment and prophylaxis as standards for treatment [6,7,20]. Access to protease inhibitors and viral load testing became fully available on 1 November 1996, when provincial funding became available. The Roche Amplicor (Roche Diagnostic Systems, Branchburg, New Jersey, USA) methodology was used for routine viral load testing (limit of detection, 400 copies/ml) until November 1997 when it was replaced by Organon Teknika (Durham, North Carolina, USA) nucleic acid sequence-based amplification (limit of detection, 40 copies/ml). Patients were routinely seen 1 month after initiating therapy and viral load measurements were checked every 3 months. At each clinic visit, data regarding antiretroviral therapy and viral load measurements were entered into a relational database.

Statistical methods

All patients starting a protease inhibitor for the first time and with a concurrent viral load measurement (i.e., at least one measurement of viral load in the 8 weeks before protease inhibitor was started) were included in the analysis. Not all patients were treated with triple combination therapy when initiating their protease inhibitor therapy. Because a more sensitive viral load assay with a lower limit of detection was introduced midway through this study, for consistency we have used a lower limit of detection of 400 copies/ml throughout the analysis, irrespective of the lower limit of detection of the viral load assay. The time to an undetectable viral load was analysed using Kaplan-Meier estimation and Cox proportional hazards models.

Patient follow-up began at the date of first protease treatment (i.e., ‘baseline’) and was censored at their last viral load measurement. In addition, in the analysis of time to reach an undetectable level and factors associated with viral load becoming undetectable, patients were censored at the date they stopped or changed their baseline treatment regimen. This approach ensured that any changes in viral load measurements could be attributed to the initial treatment regimen, rather than to subsequent changes in treatment. Patients whose viral load became undetectable during the initial 24 weeks of follow-up were then included in the analysis of the time and factors related to a subsequent detectable viral load (> 400 copies/ml), again using standard Kaplan-Meier estimation and Cox proportional hazards models [21,22].

The factors investigated included the initial CD4 lymphocyte count and viral load, whether a patient had an AIDS diagnosis, age, the number of new drugs added at the date of starting a protease inhibitor, whether a patient was treatment-naive, and any differences between the protease inhibitor in terms of reduction of viral load (indinavir versus other protease inhibitors). Logarithmic transformations of the viral load and CD4 lymphocyte count suggested that the logarithm of the viral load provided the better fitting model, as did untransformed CD4 lymphocyte count, as measured using a higher value of log-likelihood. We also considered models that modelled CD4 lymphocyte count and viral load as categorical variables, which gave similar results (data not shown). All statistical analyses were performed using SAS [23], and all P values were two-sided.

Results

In total, 243 patients started a protease inhibitor and had an accompanying viral load measurement. Table 1 describes the patients included in the analysis. The majority of the patients were men (n = 228, 93.8%) and had acquired HIV though same-sex sexual activity (n = 147, 60.5%), reflecting the HIV-infected population in South Alberta receiving care. The median age at the start of protease inhibitor therapy was 32 years (90% range, 30–32 years). Patients were varied both in terms of their baseline CD4 lymphocyte count and viral load. CD4 lymphocyte count in the 8 weeks before starting a protease inhibitor was available for 201 patients (82.7%; median, 230 × 106/l; 90% range, 30–600 × 106/l). The median viral load at baseline was 4.5 log10 copies/ml (90% range, 2.7–5.6 log10 copies/ml). Less than one-quarter of patients had an AIDS diagnosis when they first started a protease inhibitor (n = 52, 21.4%).

Table 1
Table 1:
. Patients from the Alberta Clinic Cohort.

Table 2 describes exposure to treatments amongst the patients included in the analysis. The majority of the patients were treatment-naive (n = 180, 74.1%), and in the 4 weeks prior to starting a protease inhibitor over 80% of patients were not taking any treatment at all (n = 198, 81.5%). At the time of starting a protease inhibitor, almost half of the patients simultaneously started two other new drugs (n = 108, 44.4%). Among patients who were not treatment-naive, the most common nucleoside analogue treatments previously used were zidovudine (n = 44, 18.1%) and lamivudine (n = 46, 18.9%). Fig. 1 shows the different treatments in use at baseline for the six most commonly used drugs, stratified by whether these treatments were monotherapy, dual or triple combination therapy. The majority of patients starting a protease inhibitor included the protease inhibitor as part of triple combination therapy (n = 198, 81.5%).

Table 2
Table 2:
. Treatment information.

The Kaplan-Meier graph in Fig. 2 shows the proportion of patients whose viral load became undetectable in the 9 months after starting a protease inhibitor. Of 243 patients with a viral load at baseline, 14 had no subsequent measurements, and three had undetectable viral load at baseline. Of the remaining 226 patients, 111 patients had a viral load that became undetectable. Estimates from the Kaplan-Meier graph suggested that at 24 weeks, the proportion estimated to be undetectable was 52.8% [95% confidence interval (CI), 45.2–56.6], but the number of patients becoming undetectable continued to rise through to 36 weeks. The median time to undetectable levels was 22 weeks (95% CI, 14–32).

Table 3 shows the factors associated with reaching an undetectable viral load. In a univariate analysis, a higher initial viral load at baseline was associated with a lower relative hazard (RH) of viral load becoming undetectable (RH per 1 log10 copies/ml higher viral load, 0.59; 95% CI, 0.47–0.73; P < 0.0001). Patients with a higher CD4 lymphocyte count had an increased risk of viral load becoming undetectable (RH per 100 × 106/l higher CD4 cell count, 1.22; 95% CI, 1.10–1.34; P < 0.0001). Patients who were treatment-naive at the date of starting a protease inhibitor also had an increased risk of viral load becoming undetectable (RH, 1.51; 95% CI, 1.01–2.26; P = 0.046). In a multivariate analysis, patients who were previously naive were no longer at an increased risk of achieving an undetectable viral load. Variables that remained significant predictors of undetectable viral load were a higher viral load at baseline (RH per 1 log10 copies/ml higher viral load, 0.50; 95% CI, 0.35–0.70; P < 0.0001), and a higher number of new drugs started at the date of starting a protease inhibitor (RH per each new drug, 1.54; 95% CI, 1.01–2.11; P = 0.048).

Table 3
Table 3:
. Factors associated with viral load becoming undetectable (< 400 copies/ml) after starting protease inhibitor treatment.
Fig. 1
Fig. 1:
. Drug combinations among patients starting protease inhibitors. SAQ, Saquinavir; IND, indinavir; RIT, ritonavir; ZDV, zidovudine; D4T, stavudine; 3TC, lamivudine.
Fig. 2
Fig. 2:
. Kaplan-Meier graph showing the proportion of patients whose viral load became undetectable (<400 copies/ml) in the 9 months following protease inhibitor therapy.

Fig. 3 shows the proportion of patients whose viral load became detectable again amongst 111 patients whose viral load became undetectable. In total, 21 patients experienced a re-emergence of their viral load (i.e., at least one subsequent viral load measurement > 400 copies/ml). In this analysis, patients were not censored if they subsequently started a new treatment. At 24 weeks after viral load first became undetectable, Kaplan-Meier analysis estimated that 15.5% (95% CI, 8.2–22.8%) of patients had a detectable viral load. This proportion continued to rise throughout the 36-week period; by 36 weeks over 25% of patients had experienced virological treatment failure.

Fig. 3
Fig. 3:
. Kaplan-Meier graph of the proportion of patients whose viral load became detectable again (> 400 copies/ml) amongst 111 patients whose viral load had become undetectable.

Table 4 presents the factors associated with the re-emergence of viral load (i.e., virological treatment failure) amongst those patients that started a protease inhibitor and achieved an undetectable viral load. Even though there was only a small number of patients whose viral load rose to above 400 copies/ml, there were some factors that predicted the re-emergence of viral load. In the multivariate analysis, a higher CD4 lymphocyte count was associated with a significantly lower risk of virological treatment failure (RH, 0.73; 95% CI, 0.53–1.00; P = 0.049). In this case, the number of new drugs started at the time of starting a protease inhibitor was not statistically significant. However, patients starting indinavir were at a significantly lower risk of virological treatment failure when compared with other protease inhibitor treatments (RH, 0.17; 95% CI, 0.03–0.86; P = 0.033).

Table 4
Table 4:
. Factors associated with a detectable viral load (> 400 copies/ml) among patients whose viral load had become undetectable after starting a protease inhibitor.

Discussion

This study provides important evidence from observational data in a routine clinic setting that a significant proportion of patients can attain an undetectable viral load when starting a protease inhibitor. Furthermore, it indicates that the proportion of patients reaching undetectable levels of virus continues to rise beyond 24 weeks without the addition or change to the treatment regimen. According to Kaplan-Meier estimates, almost 25% of patients who became undetectable subsequently experienced the re-emergence of detectable viral load by 9 months. Randomized clinical trials remain the gold standard for assessing the virological and clinical effects of new treatment regimens, but the results of this study emphasize that similar results can be found in observational cohorts using treatment in routine clinical practice and confirming the results of the benefits of protease inhibitors. The findings from this study support recent clinical trials of indinavir, zidovudine and lamivudine, which have reported approximately 70% of patients with viral load measurements becoming undetectable by 48 weeks of follow-up [11,12,24,25].

We found that CD4 lymphocyte count at baseline was a significant predictor of viral load becoming detectable following an undetectable viral load measurement. The reasons for this may include better tolerability, fewer side-effects and compliance among patients with higher CD4 lymphocyte counts. This result however serves to re-emphasize the importance of regular CD4 lymphocyte count measurements. In common with other investigators, we found that baseline viral load was related to the probability of becoming undetectable after adjustment for other factors, such as age and baseline CD4 lymphocyte count [16,17,26] (S. Staszewski, personal communication, 1998). Analyses of patients in clinical trials or observational studies have tended to use cross-sectional data and methods of logistic regression to determine the factors related to viral load becoming undetectable [16,27]; less common is the use of survival techniques [28]. We believe that survival techniques give a more reliable estimate of virological effects, because the technique includes information on the time taken to achieve an undetectable viral load in addition to the characteristics of those whose viral load becomes undetectable [29]. However, frequent and regular measurements of viral load during follow-up are required for this type of analysis.

It has been commonly reported that patients who were treatment-naive at the start of protease inhibitor therapy have a better virological response than those who were treatment-experienced [18,27,30,31]. The results of this study suggest that it is the number of new drugs started rather than previous treatment that is the important factor. Few studies have specifically considered the number of new drugs started, and without adjustment for this variable, treatment-naive patients would appear to do significantly better because of the strong correlation between the two variables. It is worth noting, however, that the follow-up of patients in this study is quite short and that a high proportion of patients were treatment-naive. With longer follow-up and more antiretroviral-experienced patients, treatment-naive patients may fare better simply because they have more options available to them in the future. For clinical practice it is important to start as many new antiretroviral drugs as possible when starting protease inhibitors, each selected to minimize the possibility of cross-resistance, as suggested by current treatment guidelines [6,7,20].

A minority of patients included in this analysis had started a protease inhibitor as monotherapy or as part of dual combination therapy. This reflected both the standards of practice and the limited number of therapeutic options available at the time, and may also reflect individual patient needs. We repeated our analyses including only those patients who started a protease inhibitor as part of a triple drug regimen, and the results were consistent with those presented (data not shown).

We found that patients starting indinavir were more likely to have a viral load measurement below the level of detection and also were at a lower risk of viral load becoming detectable after falling below the limit of detection than patients starting hard-gel formulation saquinavir or ritonavir. The number of patients starting ritonavir was too small to allow for a direct comparison of the efficacy of either indinavir or saquinavir hard gel with ritonavir. Saquinavir was the other most commonly used protease inhibitor in this study, which has been reported to have poor bioavailability [32] and less efficacy than the soft-gel formulation [33]. To date, their have been no direct comparisons of the virological or clinical efficacy of the protease inhibitors, and the results from an observational study should be interpreted with caution. Although we have attempted to adjust for possible confounders, such as viral load and the number of new drugs started, patients were not randomly allocated to treatments and some bias may remain for which we did not adjust. For example, we did not review patient compliance, which may be strongly related to viral load falling below the limit of detection or subsequent rebounds in viral load.

In conclusion, we have demonstrated that data from observational cohorts can help considerably in guiding treatment decisions. Patients starting protease inhibitors in combination with two new nucleoside analogues have a high probability of their viral load becoming undetectable and remaining so, particularly those with higher CD4 lymphocyte counts at the date of starting protease inhibitors.

References

1. Yerly S, Perneger TV, Hirschel B, et al.: A critical assessment of the prognostic value of HIV-1 RNA levels and CD4+ cell counts in HIV-infected patients. Arch Intern Med 1998, 158:247–252.
2. Vlahov D, Graham N, Hoover D, et al.: Prognostic indicators for AIDS and infectious disease death in HIV-infected injection drug users: plasma viral load and CD4+ cell count. JAMA 1998, 279:35–40.
3. Marschner IC, Collier AC, Coombs RW, et al.: Use of changes in plasma levels of human immunodeficiency virus type I RNA to assess the clinical benefit of antiretroviral therapy. J Infect Dis 1998, 177:40–47.
4. Havlir DV, Richmann DD: Viral dynamics of HIV: implications for drug development and therapeutic strategies. Ann Intern Med 1996, 124:984–994.
5. Feinberg M: Hidden dangers of incompletely suppressive anti-retroviral therapy. Lancet 1997, 349:1408–1409.
6. BHIVA Guidelines Coordinating Committee: British HIV association guidelines for antiretroviral treatment of seropositive individuals. Lancet 1997, 349:1086–1092.
7. Carpenter CCJ, Fischl MA, Hammer SM, et al.: Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society-USA panel. JAMA 1997, 277:1962–1969.
8. Cameron DW, Heath-Chiozzi M, Danner S, et al.: Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. Lancet 1998, 351:543–549.
9. Forrest DM, Seminari E, Montaner JSG, et al.: Changing incidence and spectrum of AIDS-defining illnesses (ADIs) in the modern antiretroviral era. Fifth Conference on Retroviruses and Opportunistic Infections. Chicago, February 1998 [abstract 179].
10. Murphy R, El-Sadr W, Cheung T, et al.: Impact of protease inhibitor containing regimens on the risk of developing opportunistic infections and mortality in the CPCRA 0134/ACTG 277 study. Fifth Conference on Retroviruses and Opportunistic Infections. Chicago, February 1998 [abstract 181].
11. Hammer S, Squires KE, Hughes MD, et al.: A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4+ cell counts of 200 per cubic millimeter or less. N Engl J Med 1997, 337:725–731.
12. Gullick RM, Mellors JW, Havlir D, et al.: Treatment with indinavir, zidovudine and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997, 337:734–739.
13. Collier AC, Coombs RW, Schoenfield DA, et al.: Treatment of human immunodeficiency virus infection with saquinavir, zidovudine and zalcitabine. N Engl J Med 1996, 334:1011–1017.
14. Egger M, Hirschel B, Francioli P, et al.: Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study. BMJ 1997, 315:1194–1199.
15. Centers for Disease Control and Prevention: Update: trends in AIDS incidence - United States 1996. MMWR 1997, 46:861–867.
16. Hogg RS, Rhone SA, Yip B, et al.: Antiviral effect of double and triple combinations amongst HIV-infected adults: lessons from the implementation of viral load-driven antiretroviral therapy. AIDS 1998, 12:279–284.
17. Rozenbaum W, Adda N, Wirbel E, Hadacek B, Schneider V, Costagliola D: Predictors and incidence of failure in 500 advanced stage HIV patients treated with indinavir. Fifth Conference on Retroviruses and Opportunistic Infections. Chicago, February 1998 [abstract 420].
18. Fatkenheuer G, Theisen A, Rockstroh J, et al.: Virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients. AIDS 1997, 11:F113–F116.
19. Raboud JM, Montaner JSG, Rae S, et al.: Predictors of duration of plasma viral load suppression. 37thInterscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, September 1997 [abstract A-14].
20. Rachlis AR, Zarowny DP, for the Canadian HIV Trials Network Antiviral Working Group: Guidelines for antiretroviral therapy for HIV infection. CMAJ 1998, 158:496–505.
21. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958, 53:457–486.
22. Cox DR, Oakes D: Analysis of Survival Data. London: Chapman and Hall; 1984.
23. SAS Institute, Inc.: SAS/STAT Users guide, Version 6, 5th Edn, Vol 2. Cary: SAS Institute, Inc.; 1989.
24. Goebel F, on behalf of the AVANTI Study Group: AVANTI II. A randomised double-blind comparative trial to evaluate combination antiretroviral regimens for the treatment of HIV-1 infection: AZT/3TC vs AZT/3TC/indinavir in antiretroviral naive patients. Sixth European Conference on Clinical Aspects and Treatment of HIV Infection. Hamburg, October 1997 [abstract 211].
25. Hirsch MS, Meibohm A, Rawlins S, et al.: Indinavir in combination with zidovudine and lamivudine in ZDV-experienced patients with CD4+ cell counts <50/mm3. Fourth Conference on Retroviruses and Opportunistic Infections. Washington, DC, January 1997 [abstract LB6A].
26. Demeter L, Hughes M, Fischl M, et al.: Predictors of virological and clinical response to indinavir (IDV)+ZDV+3TC or ZDV+3TC. Fifth Conference on Retroviruses and Opportunistic Infections. Chicago, February 1998 [abstract 509].
27. Fessel WJ, Hurley LB: Outcomes of triple therapy that included a protease. Fifth Conference on Retroviruses and Opportunistic Infections. Chicago, February 1998 [abstract 145].
28. Yu G, Chang Y, Greenberg SL, et al.: Durability of virological response in patients with Viracept (Nelfinavir mesylate) in combination with zidovudine and lamivudine. Sixth European Conference on Clinical Aspects and Treatment of HIV Infection. Hamburg, October 1997 [abstract 410].
29. De Gruttola V, Hughes MD, Gilbert P, et al.: Trial design in the era of highly effective antiviral drug combinations for HIV infection. AIDS 1998, 12(Suppl. A):S144–S156.
30. Hill A, Opravil M, Demas R: Prediction of long-term HIV-1 RNA suppression during AZT/3TC treatment. Sixth European Conference on Clinical Aspects and Treatment of HIV Infection. Hamburg, October 1997 [abstract 112].
31. Perez-Elias MJ, Antela A, Casado JL, et al.: Comparison between protease inhibitor therapy with or without new nucleoside analogues. Sixth European Conference on Clinical Aspects and Treatment of HIV Infection. Hamburg, October 1997 [abstract 361].
32. Moyle G: Saquinavir: a review of its development, pharmacological properties and clinical use. Exp Opin Invest Drugs 1996, 5:155–167.
33. Mitsuyasu RT, Skolnik PR, Cohen SR et al.: Activity of the soft gelatin formulation of saquinavir in antiretroviral naive patients. AIDS 1998, 12:F103–F109.
Keywords:

Viral load; protease inhibitors; undetectability; progression

© 1998 Lippincott Williams & Wilkins, Inc.