Simplification is not so easy: Reported By Graeme Moyle, MD, Chelsea & Westminster Hospital, London UK

XIII NATAP at the Durban World AIDS Conference 2000
Durban, South Africa, July 9-14

Simplification is not so easy:
Reported By Graeme Moyle, MD, Chelsea & Westminster Hospital, London UK

The introduction of potent three (or more) drug antiretroviral therapy regimens (highly active antiretroviral therapy, HAART) has dramatically modified the natural history of HIV-1 infection. However, HAART regimens are unable to eradicate HIV-1 infection, thus establishing the current HIV therapeutic paradigm of giving antiretroviral therapy for an indefinite period. Initial studies evaluating treatment deintensification to more convenient maintenance regimens following, generally, 24 weeks of induction to <50 copies/ml with HAART regimens is not able to maintain the suppression of HIV replication [1ń3]. The failure in these studies may have been due an insufficiently long induction phase.

In patients involved in the ADAM study [1], a second cohort of patients were evaluated to test the effect of a longer period of induction therapy on the feasibility of a treatment deintensification [4]. Antiretroviral therapy naive patients were treated with a 4 drug induction regimen (d4T + 3TC + saquinavir (initially as hard gel) (SQV) + nelfinavir (NFV)) for 26 or 50 weeks. Randomization at week 26 was discontinued following an interim analysis that showed inferior suppression of viral replication during maintenance therapy [1]. At week 50, patients were randomized to maintenance therapy (either d4T + NFV or SQV + NFV) or continued quadruple therapy if the plasma HIV-1 RNA levels at weeks 48 and 49 were both below the limit of quantification (<50 copies/ml). After randomization, monthly monitoring of viral load in plasma was performed. Treatment failure was defined as two consecutive HIV-1 RNA measurements >100 copies/mL. Of original 65 patients who commence the induction regimen, 16 patients had been randomized at week 26. Of the remaining 49 patients, 17 patients were randomized at week 50. Ten patients were randomized to either D4T/NFV (6) or SQV/NFV (4). In both arms one patient withdrew after randomization. Treatment failure was observed in 4/8 patients who deintensified compared to 1/5 evaluable patients on quadruple therapy (p=0.56). In the patients randomized to deintensify at week 26 and at week 50, kaplan-Meier analysis indicated time to > 400 HIV-1 RNA copies/mL in plasma was comparable.

The authors concluded a longer period of indcution does not postpone recurrence of viral replication following deintensification [4].

Given this disappointment, the next best thing may be to simplify regimen administration, reducing the frequency of dosing of tablet volume. Several studies looking at different drugs evaluated this possibility. Based on pharmacokinetic data presented last year [5] which indicated a dose of 100mg of ritonavir with 1200mg of indinavir resulted in higher indinavir exposure and a similar or higher trough level of indinavir to tid dosing a case-control study was performed at two Italian clinics. Patients on an indinavir-containing regimen and with viral load <50 copies/ml were offered change to once daily indinavir/ritonavir. Matched controls were selected based from the clinics database.

Twelve patient have completed 16 weeks of follow-up. Baseline characteristics included viral load <50 for 16 months and CD4 369 cells/mm³. No viral rebound to >400 have occurred in simplification patients versus one in the control case. However, 2 simplfication and 3 control patients have had a viral measurement >50 at week 16. It is not known if these represent ëblipsí or not. Two simplification patients and one control have reported renal calculi [6]. This may have been expected given the peak indinavir levels reported for this regimen are around 80% higher than with tid dosing.

The pharmacokinetics of some NNRTIs and nucleoside analogues favour once daily (QD) dosing. Results of a Spanish study evaluating once daily ddI and nevirapine versus twice daily dosing, in each case with stavudine in asymptomatic antiretroviral naive HIV-1 infected patients with CD4+ T cell count >500 x 106/L and viral load > 5000 copies /ml were also discussed today. Patients were randomly assigned to QD (N = 45) or BID (N = 44). Baseline characteristic were not presented. The mean reduction in VL at month 12 was -1.84 (QD) versus -1.78 (BID) (p = 0.91) with the proportion of patients below 200 c/ml at 12 months by intent-to-treat (ITT) analysis being 73% (QD) and 68% (BID), and below 5 c/ml: (ITT) 40% (QD) and 45% (BID). No differences in CD4 count increase was observed. Tonsillar biopsies were performed in a subset of 11 patients with a plasma VL at month 12 below 5 copies/ml, 5 had detectable lymphoid VL (median: 7750 c/mg of tissue, range: 1020-33077). Eight percent of patients changed treatment due to side effects [7].

Whilst data support the use of once daily ddI and nevirapine in antiretroviral naive patients the lymphoid viral load data raise some concerns regarding the potential durability of this response.

Another novel approach to once daily dosing was to combine the two once daily NNRTIs, efavirenz and nevirapine with ddI. The idea behind combining NNRTIs is that the total NNRTI exposure will be increased, potentially leading to additive antiviral effects. Limiting the nucleoside analogue load in this regimen may also have long term tolerability advantages. This study evaluated fifteen treatment-naive and 11 treatment-experienced patients. Treatment was NVP (400 mg qd) plus EFV (600 mg qd) plus ddI (400 mg qd), thus no adjustment for a pharmacokinetic interaction which diminished efavirenz exposure around 30% was made ( in an ongoing study of this combination efavirenz is dosed at 800mg/day with standard dose nevirapine). Amongst the treatment-naive patients the mean baseline VL was 4.59 log₁₀ copies/mL, and the mean baseline CD4+ was 351 cells/mm³; after 9 months of therapy, 12/12 evaluable patients had VL <400 copies/mL, and CD4+ had increased by mean 351 cells/mm³. At baseline, 9/11 treatment-experienced patients had a VL <400 copies/mL, and mean CD4+ of 368 cells/mm³; after 9 months, 9/9 had VL <400 copies/mL , and CD4+ had increased by mean 203 cells/mm3. Five of the 26 patients (19%) discontinued therapy, 2 for rash, 3 for CNS effects. This pilot study suggest that a double NNRTI therapy is a potentiall attractive approach and further evaluation of once-daily NVP+EFV+ddI is warranted.

1. Reijers MH, Weverling GJ, Jurriaans S, Wit FW, Weigel HM, Ten Kate RW et al. Maintenance therapy after quadruple induction therapy in HIV-1 infected individuals: Amsterdam Duration of Antiretroviral Medication (ADAM) study. Lancet 1998; 352: 185ń190.

2. Havlir DV, Marschner IC, Hirsch MS, Collier AC, Tebas P, Bassett RL et al. Maintenance antiretroviral therapies in HIV-1 infected subjects with undetectable plasma HIV RNA after triple-drug therapy.N Eng J Med 1998; 339: 1261ń8.

3. Pialoux G, Raffi F, Brun-Vezinet F, MeiffrČdy V, Flandre P, Gastaut JA et al. A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1 infected patients.N Eng J Med 1998; 339: 1269ń1276.

4. Reijers MH, Weverling GJ, Jurriaans S, et al. The ADAM study: maintenance therapy after 50 weeks of induction therapy. XIII International AIDS Conference, Durban, July 9-14, 2000: abstract TuPpA1154

5. Saah A, 39^th ICAAC

6. Maggiolo F, Rizzi M, Finazzi G, Suter F Once-a-day indinavir therapy in virologically controlled HIV+ persons . XIII International AIDS Conference, Durban, July 9-14, 2000: abstract TuPpA1155

7. Felipe G, Hernando K, Maria Antonia S, et al. An open randomized study comparing d4T + ddI and nevirapine (Qd) vs d4T + ddI and nevirapine (Bid) in antiretroviral naive chronic HIV-1 infected patients in very early stages: Spanish scan study. Final results. XIII International AIDS Conference, Durban, July 9-14, 2000: abstract TuPpA1156

8. Jordan W, Jefferson R, Yemofio F, et al. Nevirapine (NVP) + efavirenz (EFV) + didanosine (ddI): a very simple, safe, and effective once-daily regimen. XIII International AIDS Conference, Durban, July 9-14, 2000: abstract TuPeB3207.