Foscarnet salvage therapy for patients with latestage HIV disease and multiple drug resistance

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1 Antiviral Therapy 11: Foscarnet salvage therapy for patients with latestage HIV disease and multiple drug resistance Ana Canestri 1, Jade Ghosn 1, Marc Wirden 2, Françoise Marguet 1, Nadine Ktorza 1, Imane Boubezari 1, Stéphanie Dominguez 1, Philippe Bossi 1, Eric Caumes 1, Vincent Calvez 2 and Christine Katlama 1 * 1 Département des Maladies Infectieuses, Hôpital Pitié-Salpétriêre, Paris, France 2 Département de Virologie, Hôpital Pitié-Salpétriêre, Paris, France *Corresponding author: Tel: ; Fax: : christine.katlama@psl.ap-hop-paris.fr Objective: To evaluate the efficacy of foscarnet on HIV infection in patients with late-stage HIV disease and multiple drug resistance. Methods: Three drugs experienced patients with plasma viral load (pvl) >50,000 copies/ml and CD4 + T-cell counts <100/mm 3 were eligible for this open-label, single-arm, add-on pilot study. Foscarnet induction therapy consisted of 5 g intravenously twice daily for 6 weeks, in addition to a stable antiretroviral regimen. Patients with at least 1 log 10 decrease in pvl at week 6 (W6), were given foscarnet 5 g intravenously twice daily on two consecutive days each week. Primary endpoint was the virological response rate at W6. Results: Eleven patients were enrolled with a median baseline pvl at 5.16 log 10 copies/ml, median CD4 + T-cell count at 10/mm 3 and median number of mutations of 9, 2 and 12 associated with resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nrtis and protease inhibitors, respectively. One patient discontinued foscarnet at W2 because of renal toxicity. In an intentto-treat analysis, the median change in pvl from baseline was log 10 copies/ml at W2 and log 10 copies/ml at W6. Eight out of eleven patients had a fall in pvl of at least 1 log 10 at W6, and six started maintenance therapy. The median fall in pvl after 12 weeks of maintenance therapy was log 10 copies/ml in the four patients who reached W12, and the median increase of CD4 + T-cell count was 60/mm 3. Conclusion: In patients with HIV mutations conferring resistance to all antiretroviral drug classes, foscarnet markedly reduced plasma HIV load and improved immunological status. Introduction Many patients with long-standing HIV infection have multidrug resistance. Virological failure remains frequent despite the arrival of new agents like enfuvirtide and tipranavir, and investigational drugs such as TMC-114 [1 5]. In trials of salvage treatments, the proportions of patients who had at least a 1 log 10 reduction in plasma viral load (pvl) at week 24 (W24) were 43% in the Toro study [1], 41% in the RESIST study [4] and 77% in the POWER study [5]. These studies showed that lower baseline pvls were associated with better virological responses. In another study, one-third of patients with viruses resistant to three drug classes died or had new AIDS-defining events during follow-up [6]. Foscarnet, a pyrophosphate analogue, prevents pyrophosphate exchange and thereby inhibits DNA chain elongation catalysed by a variety of viral DNA polymerases (cytomegalovirus [CMV], herpes simplex virus, varicella-zoster virus, Epstein-Barr virus), including HIV-1 reverse transcriptase (RT) [7]. Thymidine-associated mutations (TAMs) appear to render HIV hypersusceptible to foscarnet in vitro [8,9]. In the pre-highly active antiretroviral therapy (HAART) era, foscarnet was mostly given to patients with CMV infection and was found to lower plasma HIV RNA levels [10 14], but its intravenous administration and nephrotoxicity, together with the arrival of more convenient antiretroviral drugs, led to a loss of interest. In this study, we evaluated the efficacy and tolerability of foscarnet in patients with late-stage HIV disease and no other therapeutic options. Methods Study design This open-label, single-centre, add-on pilot study examined the efficacy and safety of foscarnet induction therapy given for 6 weeks to patients with severe immunodeficiency, virological failure and multidrug-resistant HIV. Patients in whom pvl levels fell by at least 1 log 10 after 6 weeks were offered foscarnet maintenance therapy (MT) International Medical Press

2 A Canestri et al. Patients Patients were eligible if they had HIV-RNA values above 50,000 copies/ml and CD4 + T-cell counts below 100/mm 3 while on a stable antiretroviral regimen for at least 8 weeks (comprising at least four drugs), and if they had previously received at least three antiretroviral drug classes. Genotypic viral resistance had to include at least three TAMs, plus at least one mutation associated with resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and two primary mutations associated with resistance to protease inhibitors (PIs), according to the International AIDS Society-USA list (May 2004). The serum creatinine concentration had to be below 130 µmol/l at baseline. Study treatment Foscarnet induction therapy consisted of 5 g intravenously twice daily, concomitantly with 1,500 ml of normal saline, and calcium and phosphorus supplementation. This fixed dose corresponds to a median weight-based dose of 85 mg/kg twice daily on the basis of median weight of French HIV-infected patients with end-stage disease. Patients were hospitalized for a minimum of 10 days in order to assess tolerability. The only permitted changes in antiretroviral therapy were the addition of zidovudine (AZT; 300 mg twice daily) if AZT was not included in the baseline regimen (or the addition of stavudine [d4t] 30 mg twice daily in case of AZT intolerance), and tenofovir discontinuation in order to avoid potential additive nephrotoxicity. Induction therapy lasted 6 weeks. Patients who had at least a 1 log 10 fall in pvl at W6 were offered MT, consisting of foscarnet 5 g intravenously twice daily on two consecutive days per week. Ongoing antiretroviral therapy could be optimized before starting MT. Clinical and laboratory evaluations The patients had weekly clinical examinations and efficacy and safety assessments (biochemistry, viral load assay and CD4 + T-cell count). Plasma HIV-RNA was quantified with the Amplicor Monitor assay (v1.5; Roche Diagnostics, Meylan, France) which has a detection limit of 200 copies/ml. The RT gene was sequenced (codons 1 240) by means of automated population-based full-sequence analysis (ABI 3100 Genetic Analyser, PE Applied Biosystems, Foster City, CA, USA) at baseline, at the end of induction therapy, and monthly during maintenance therapy. All mutations in the RT and protease genes leading to amino acid changes were analysed, including mutations probably linked to foscarnet resistance [8,9,15]. Ophthalmoscopic examination, cytomegalovirus pp65 antigenaemia and blood culture on Lowenstein-Jensen medium were performed monthly. Endpoints for efficacy The primary endpoint was the proportion of patients experiencing a decrease in HIV-RNA of at least 1 log 10 at W6 compared with baseline. Secondary endpoints included changes in HIV RNA and in the CD4 + T-cell count at W6 compared with baseline; changes in HIV RNA and the CD4 + T-cell count during maintenance therapy; changes in the HIV genotypic resistance profile; and the safety and tolerability of foscarnet. Results Baseline characteristics A total of 11 men were enrolled between April 2004 and January One patient discontinued foscarnet at week 2 because of toxicity. The remaining 10 patients were assessable at W6. The median age of the 11 patients was 49 years (range: 33 75). All had been extensively treated, having been exposed to a median of 14 antiretroviral drugs (range: 11 16), including enfuvirtide (8/11) and tipranavir (7/11), over a median period of 12 years (range: ). The median baseline pvl was 5.18 log 10 copies/ml (range: ) and the median baseline CD4 + T-cell count was 10/mm 3 (range: 1 49). Ongoing antiretroviral therapy at baseline is shown in Table 1. Eight patients started AZT and one d4t concomitantly with foscarnet; the remaining two were already on AZT in their background regimen. All the patients had experienced AIDS-defining events, and nine patients had at least one active opportunistic infection at baseline, consisting of oesophageal candidiasis (n=3), disseminated Mycobacterium aviumintracellulare complex (MAIC) infection (n=2), lymphoma, CMV retinitis, HIV encephalitis, chronic diarrhoea and cryptosporidiosis (one case each). The median body weight was 65 kg (range: 56 74). Median creatinine clearance was 80 ml/min (range: ) and median haemoglobin was 9.8 g/dl (range: ); 5/11 patients (45%) had grade 1 anaemia. As shown in Table 2, all the patients harboured highly mutated viruses, with a median of 24 resistance mutations (range: 18 28), including nine associated with NRTI resistance (including four TAMs), two associated with NNRTI resistance and 12 associated with PI resistance. Five patients had mutations associated with enfuvirtide resistance. Four patients had resistance mutations reported to influence foscarnet susceptibility (K65R in patient 1, H208Y in patient 6, L228R in patient 10, and H208Y in patient 11) International Medical Press

3 Foscarnet salvage therapy in late-stage HIV Table 1. Characteristics at baseline, and evolution of HIV RNA and CD4 + T-cell count during induction and maintenance phases of foscarnet therapy Baseline characteristics W6 Maintenance therapy Background CD4 CD4 HIV-RNA VL log 10 CD4 HIV-RNA VL log 10 treatment cells/ HIV-RNA cells/ copies/ from Background ARV Reason for cells/ copies/ from Patients at baseline* mm 3 copies/ml mm 3 ml baseline optimization Time discontinuation mm 3 ml baseline 1 TZV 4 195, , TZV/ATZr/T20* W4 Failure 73 80, TZV/TPVr/T , < AZT switched W33 TMC , to d4t 3 TZV/TPV/SQV/ , , TMC-114 LPVr 4 TZV/ddI/TPV/ 14 52, , TZV/ddI/ATZ/ W29 TMC , SQV/LPVr/T20 APVr/T20* 5 ABC/d4T/3TC/ 2 106,000 Stop at W2 for oedema TPVr/T20 6 TZV-TPV , T20* W24 TMC , CBV/IDVr 5 150, , TC/d4T/TPV/ W12 Failure 17 84, APVr/T20* 8 CBV/APVr 6 138, < CBV/LPV/APV/ W14 Failure 29 25, T20* 9 TZV/APV/ATZ/ 1 4,580, , TMC-114 SQVr/T20 10 TZV/ddI/APVr , TMC TZV/APV/ATZ/ , , TMC-114 SQVr/T20 *8 weeks stable treatment except AZT or d4t addition or TDF discontinuation. CD4 + T-cell count expressed as absolute value. Recycled T20. 3TC, lamivudine; ABC, abacavir; APV, amprenavir; ATZ, atazanavir; AZT, zidovudine; CBV, zidovudine + lamivudine; d4t, stavudine; ddi, didanosine; IDV, indinavir; LPV, lopinavir; SQV, saquinavir; T20, enfuvirtide; TDF, tenofovir; TMC114, darunavir; TPV, tipranavir; TZV, zidovudine + lamivudine + abacavir; VL, viral load; W, week; X/r, boosted with low-dose ritonavir. Changes in HIV pvl and in the CD4 + T-cell count during induction therapy Eight patients had at least a 1-log 10 reduction in pvl at W6 (8/11, 73% in the intent-to-treat analysis; 8/10, 80% in the on-treatment analysis). The median change in HIV RNA from baseline was 1.39 log 10 copies/ml (range: 0.45 to 2.39) at W1, 1.99 log 10 copies/ml (range: 0.50 to 2.49) at W2, 1.82 log 10 copies/ml (range: 1.02 to 2.88) at W4, and 1.79 log 10 copies/ml (range: 2.88 to +0.11) at W6 (Figure 1). The median increase in the CD4 + T-cell count was 28/mm 3 (range: 0 111) at W6. Five patients (50%) who received the full induction course had CD4 + T-cell counts above 50/mm 3 at W6. Maintenance therapy Of the eight patients who had at least a 1 log 10 reduction in pvl at W6, six started foscarnet maintenance therapy, and the remaining two patients were enrolled in a Phase II trial of a new antiretroviral agent. Of these six patients, two discontinued foscarnet because of virological failure: patient 1 after 4 weeks and patient 7 after 12 weeks. The median change in pvl after 12 weeks of MT was 0.85 log 10 copies/ml (n=4) (range: 0.04 to 2.81), and the median change in the CD4 + T-cell count was +60 cells/mm 3 (range: ). At 24 weeks, three patients had received MT and had sustained pvl below 5,000 copies/ml. Changes in genotypic resistance No change in baseline mutations associated with NRTI or PI resistance was observed during either induction or maintenance therapy. One patient (2) had selected the K219R foscarnet mutation at the end of induction phase (W6; Table 2). Two patients (4 and 6) also harboured virus with this mutation at W16 and W24 of MT, respectively. Despite this, these three patients had virological response at the moment of resistance emergence ( 2.88, 0.77 and 2.55 log 10 ) and during the study (Table 1). No other change was observed on the RT gene sequences in the 11 patients. Antiviral Therapy 11:5 563

4 A Canestri et al. Table 2. Resistance mutations at baseline and during follow-up T20 mutations* Foscarnet mutations Patient RT inhibitor mutations* (baseline ) PI major mutations* (baseline ) Baseline Emergence (at) Baseline Emergence (at) 1 A62V, K65R, D67N, V75I, Y115F, L33F, M46I, V82C, I84V, L90M None K65R F116Y, V118I, Q151M, Y181C, M184V, G190A, T215V, K219Q 2 M41L, E44D, D67N, L74V, L100I, L33F, M46I, V82T V38A None K219R (W6) K103N, V118I, M184V, L210W, T215Y 3 D67N, T69D, V75I, F77L, K103N, Y181C, L33F, M46I, V82T, I84V, L90M None None Y115F, F116Y, V118I, Q151M, T215F, K219Q 4 M41L, D67N, T69D, V75M, V118I, V106M, L33F, M46I, V82T, I84V Q40H, None K219R (W16) Y188L, M184V, L210W, T215Y L45M 5 M41L, L74V, V118I, Y181C, M184V, G190A, M46L, V82C, L90M V38A/V None L210W, T215Y 6 M41L, E44D, D67N, L74I, V75T, V118I, M46I, I84V, L90M N42T, H208Y K219R (W24) M184V, G190A, T215F, K219Q N43D 7 M41L, E44D, D67N, V75M, F77L, V118I, L33F, M46I, V82A, I84V None G36D/G (W12) None M184V, Y188L, L210W, T215Y 8 M41L, E44D, D67N, L74I, Y181C, G190A, M46I, I84V, L90M V38A, None M184V, L210W, T215Y, K219N L44M 9 M41L, D67N, T69D, L74I, V75S, V118I, L33I, M46I, I84V, L90M None None Y181C, M184V, G190A, L210S, T215F, K219W 10 M41L, E44D, V118I, M184V, T215Y, L33F, M46I, I50V, V82T, L90M None L228R K103N, K219N 11 M41L, E44D, D67N, L74V, L100I, K103N, V118I, M184V, L210W, T215Y, K219N L33F, G48M, V82A, I84V, L90M None G36D (W6) H208Y *According to the IAS-USA List. No emergence of mutation during the study except for patient 3 with emergence of E203K, F227C, L228S polymorphisms at week 6. PI, protease inhibitor; RT, reverse transcriptase; W, week. Tolerability Only one patient discontinued foscarnet during the induction phase (W2), because of oedema with renal impairment and proteinuria; renal function recovered Figure 1. Changes in HIV plasma VL during the 6-weekinduction phase W1 W2 W3 W4 W5 W6 n VL, viral load; W, week days after foscarnet discontinuation. One patient had an infection associated with an intravenous device, which resolved on antimicrobial chemotherapy. No cases of renal impairment occurred during MT. AZT was discontinued in three patients for anaemia during induction phase (two grade 1 and one grade 2); they were switched to d4t. Median haemoglobin was 9.0 g/dl (range: ) at W6 and 7/11 patients (64%) had anaemia less than or equal to grade 2. One patient experienced genital ulceration that improved with local hygiene and treatment. Clinical events and follow-up No new AIDS-defining events occurred during the study period. Four patients had a clinical improvement in ongoing AIDS-related disorders (HIV encephalitis, cryptosporidiosis, CMV retinitis and severe chronic diarrhoea). Two patients (5 and 9) died of progressive HIV disease, 2 and 3 months after foscarnet discontinuation International Medical Press

5 Foscarnet salvage therapy in late-stage HIV Discussion In this pilot study of foscarnet therapy in HIV-infected patients with virological failure after exposure to at least three classes of antiretroviral drugs, pvl fell by a median of 1.79 log 10 copies/ml after 6 weeks of treatment, and the CD4 + T-cell count rose by a median of 28/mm 3. All patients had a sharp decline in pvl at W2, which was maintained at W6 in 9/10 patients. As foscarnet was added to a failing antretroviral regimen, it is very likely that the observed virological efficacy was due to foscarnet itself. Viral resistance was probably the main reason for virological failure at study entry, as the patients had adequate drug concentrations (not shown) but a median of 21 resistanceassociated mutations (range: 16 25). Similar results have been reported by Mathiesen et al. [14], who gave foscarnet salvage therapy to seven patients and observed a fall in pvl of 1.8 log 10 after 2 weeks. The precise mechanism of foscarnet action is unclear. All our patients had TAMs (median 4, range: 3 5), which increase HIV susceptibility to foscarnet [8,9]. Foscarnet is reported to restore susceptibility to thymidine analogues by attenuating the primerunblocking mechanism, which is one of the main mechanisms involved in NRTI resistance [8], and it is noteworthy that all our patients were receiving NRTIs at enrolment. Tachedjian et al. [9] have reported that mutations selected by foscarnet can restore AZT efficacy, and this is why we added AZT to each patient s drug regimen, if necessary. It is interesting to note that virological efficacy was maintained in our study even though four patients had baseline mutations thought to reduce foscarnet efficacy and another three patients acquired such mutations during treatment. Full-dose foscarnet therapy is unrealistic in the longterm because of potential nephrotoxicity and the inconvenience of intravenous infusion. Mathiesen et al. [14] used half the standard daily dose of foscarnet for maintenance therapy, but this resulted in a blunted virological response ( 0.6 log 10 ), probably owing to inadequate trough levels or acquisition of foscarnet resistance. We opted for an intermittent maintenance regimen, administering full-dose foscarnet on two consecutive days per week (then five days off), for reasons of patient convenience and virus cycling. The immunological benefit noted during the induction phase (5/10 assessable patients had CD4 + T-cell counts above 50/mm 3 ) persisted during maintenance therapy, and no clinical events were observed in these severely immunocompromised patients. Overall, foscarnet was well-tolerated. Renal toxicity occurred in one patient, but resolved rapidly after foscarnet discontinuation. Several strategies had been evaluated to significantly reduce viral replication in patients with multi-resistant viruses. Short-term treatment interruption followed by gigatherapy, including at least one active drug to which the patient has never been exposed, is associated with a virological benefit [16], whereas a 12-week treatment interruption failed to restore the antiviral efficacy of salvage gigatherapy comprising only previously used drugs, and was clinically deleterious [17 20]. By now, the best option for heavily treated patients is a regimen containing at least two active agents [1,2], but this is not always possible. Although our findings need to be confirmed in larger studies, they suggest that foscarnet might allow patients with very advanced HIV disease and no other treatment option to survive until new active therapies become available. References 1. Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 2003; 348: Lalezari JP, Henry K, O Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003; 348: Tipranavir favored in RESIST-2. AIDS Patient Care STDS 2005, 19: Valdez HM, Kohlbrenner V, Mayers D. Tipranavir/ritonavir (TPV/r) 500 mg/200 mg BID drives week 24 viral load (VL) below 400 copies/ml when combined with a second active drug (T-20) in protease inhibitor experienced HIV+ patients. 3rd IAS conference on HIV Pathogenesis and Treatment. Rio de Janeiro July Abstract WeOa Katlama CCD, De Backer K, Lefebvre E, et al. TMC114/r outperforms investigator-selected PI(s) in 3-class-experienced patients: week 24 primary analysis of POWER 1 (TMC114-C213). 3rd IAS conference on HIV Pathogenesis and Treatment. Rio de Janeiro July Abstract WeOa LB Zaccarelli M, Tozzi V, Lorenzini P, et al. Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients. AIDS 2005; 19: Chrisp P, Clissold SP. Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis. Drugs 1991; 41: Meyer PR, Matsuura SE, Zonarich D, et al. Relationship between 3 -azido-3 -deoxythymidine resistance and primer unblocking activity in foscarnet-resistant mutants of human immunodeficiency virus type 1 reverse transcriptase. J Virol 2003; 77: Tachedjian G, Mellors J, Bazmi H, Birch C, Mills J. Zidovudine resistance is suppressed by mutations conferring resistance of human immunodeficiency virus type 1 to foscarnet. J Virol 1996; 70: Devianne-Garrigue I, Pellegrin I, Denisi R, et al. Foscarnet decreases HIV-1 plasma load. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 18: Segondy M, Montes B, Delmas B, Leclercq C, Janbon F, Reynes J. Changes in HIV-1 RNA plasma level in patients treated with foscarnet. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 14: Balfour HH Jr, Fletcher CV, Erice A, et al. Effect of foscarnet on quantities of cytomegalovirus and human immunodeficiency virus in blood of persons with AIDS. Antimicrob Agents Chemother 1996; 40: Antiviral Therapy 11:5 565

6 A Canestri et al. 13. Bergdahl S, Jacobsson B, Moberg L, Sonnerborg A. Pronounced anti-hiv-1 activity of foscarnet in patients without cytomegalovirus infection. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 18: Mathiesen S, Roge BT, Weis N, Lundgren JD, Obel N, Gerstoft J. Foscarnet used in salvage therapy of HIV-1 patients harbouring multiple nucleotide excision mutations. AIDS 2004; 18: Mathiesen S, Dam E, Roge B, Laursen AL, Gerstoft J, Clavel F. Long-term foscarnet therapy remodels thymidine analogue mutations and reverse resistance to zidovudine. 14th International HIV Drug Resistance Workshop June 2005, Québec City, Canada. Abstract Katlama C, Dominguez S, Gourlain K, et al. Benefit of treatment interruption in HIV-infected patients with multiple therapeutic failures: a randomized controlled trial (ANRS 097). AIDS 2004; 18: Ghosn J, Wirden M, Ktorza N, et al. No benefit of a structured treatment interruption based on genotypic resistance in heavily pretreated HIV-infected patients. AIDS 2005; 19: Kantor R, Shafer RW, Follansbee S, et al. Evolution of resistance to drugs in HIV-1-infected patients failing antiretroviral therapy. AIDS 2004; 18: Lawrence J, Mayers DL, Hullsiek KH, et al. Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. N Engl J Med 2003; 349: Ruiz L, Ribera E, Bonjoch A, et al. Role of structured treatment interruption before a 5-drug salvage antiretroviral regimen: the Retrogene Study. J Infect Dis 2003; 188: Accepted for publication 18 March International Medical Press