Foscarnet Salvage Therapy for Patients with Late- Stage HIV Disease And

Antiviral Therapy 11:561–566 Foscarnet salvage therapy for patients with late- stage HIV disease and multiple drug resistance Ana Canestri 1, Jade Ghosn1, Marc Wirden 2, Françoise Marguet 1, Nadine Ktorza1, Imane Boubezari 1, Stéphanie Dominguez 1, Philippe Bossi 1, Eric Caumes1, Vincent Calvez 2 and Christine Katlama1*

1Département des Maladies Infectieuses, Hôpital Pitié-Salpétriêre, Paris, France 2Département de Virologie, Hôpital Pitié-Salpétriêre, Paris, France

*Corresponding author: Tel: +33 1 4216 0130; Fax: +33 1 4216 0126: E-mail: [email protected]

Objective: To evaluate the efficacy of foscarnet on HIV 2 and 12 associated with resistance to nucleoside reverse infection in patients with late-stage HIV disease and transcriptase inhibitors (NRTIs), non-NRTIs and protease multiple drug resistance. inhibitors, respectively. One patient discontinued Methods: Three drugs experienced patients with plasma foscarnet at W2 because of renal toxicity. In an intent- viral load (pVL) >50,000 copies/ml and CD4+ T-cell counts to-treat analysis, the median change in pVL from baseline 3 <100/mm were eligible for this open-label, single-arm, was -1.99 log10 copies/ml at W2 and -1.79 log10 add-on pilot study. Foscarnet induction therapy consisted copies/ml at W6. Eight out of eleven patients had a fall of 5 g intravenously twice daily for 6 weeks, in addition in pVL of at least 1 log10 at W6, and six started mainte- to a stable antiretroviral regimen. Patients with at least nance therapy. The median fall in pVL after 12 weeks of

1 log10 decrease in pVL at week 6 (W6), were given maintenance therapy was -0.85 log10 copies/ml in the foscarnet 5 g intravenously twice daily on two consecu- four patients who reached W12, and the median increase tive days each week. Primary endpoint was the virological of CD4+ T-cell count was 60/mm3. response rate at W6. Conclusion: In patients with HIV mutations conferring Results: Eleven patients were enrolled with a median resistance to all antiretroviral drug classes, foscarnet + baseline pVL at 5.16 log10 copies/ml, median CD4 T-cell markedly reduced plasma HIV load and improved count at 10/mm3 and median number of mutations of 9, immunological status.

Introduction

Many patients with long-standing HIV infection have render HIV hypersusceptible to foscarnet in vitro [8,9]. multidrug resistance. Virological failure remains frequent In the pre-highly active antiretroviral therapy despite the arrival of new agents like enfuvirtide and (HAART) era, foscarnet was mostly given to patients tipranavir, and investigational drugs such as TMC-114 with CMV infection and was found to lower plasma [1–5]. In trials of salvage treatments, the proportions of HIV RNA levels [10–14], but its intravenous adminis- patients who had at least a 1 log10 reduction in plasma tration and nephrotoxicity, together with the arrival of viral load (pVL) at week 24 (W24) were 43% in the Toro more convenient antiretroviral drugs, led to a loss of study [1], 41% in the RESIST study [4] and 77% in the interest. In this study, we evaluated the efficacy and POWER study [5]. These studies showed that lower tolerability of foscarnet in patients with late-stage HIV baseline pVLs were associated with better virological disease and no other therapeutic options. responses. In another study, one-third of patients with viruses resistant to three drug classes died or had new Methods AIDS-defining events during follow-up [6]. Foscarnet, a pyrophosphate analogue, prevents Study design pyrophosphate exchange and thereby inhibits DNA This open-label, single-centre, add-on pilot study examined chain elongation catalysed by a variety of viral DNA the efficacy and safety of foscarnet induction therapy given polymerases (cytomegalovirus [CMV], herpes simplex for 6 weeks to patients with severe immunodeficiency, viro- virus, varicella-zoster virus, Epstein-Barr virus), logical failure and multidrug-resistant HIV. Patients in including HIV-1 reverse transcriptase (RT) [7]. whom pVL levels fell by at least 1 log10 after 6 weeks Thymidine-associated mutations (TAMs) appear to were offered foscarnet maintenance therapy (MT).

Patients Ophthalmoscopic examination, cytomegalovirus pp65 Patients were eligible if they had HIV-RNA values antigenaemia and blood culture on Lowenstein-Jensen above 50,000 copies/ml and CD4+ T-cell counts below medium were performed monthly. 100/mm3 while on a stable antiretroviral regimen for at least 8 weeks (comprising at least four drugs), and Endpoints for efficacy if they had previously received at least three anti- The primary endpoint was the proportion of patients retroviral drug classes. Genotypic viral resistance had experiencing a decrease in HIV-RNA of at least 1 log10 to include at least three TAMs, plus at least one muta- at W6 compared with baseline. Secondary endpoints tion associated with resistance to non-nucleoside included changes in HIV RNA and in the CD4+ T-cell reverse transcriptase inhibitors (NNRTIs) and two count at W6 compared with baseline; changes in HIV primary mutations associated with resistance to RNA and the CD4+ T-cell count during maintenance protease inhibitors (PIs), according to the therapy; changes in the HIV genotypic resistance International AIDS Society-USA list (May 2004). The profile; and the safety and tolerability of foscarnet. serum creatinine concentration had to be below 130 µmol/l at baseline. Results Study treatment Baseline characteristics Foscarnet induction therapy consisted of 5 g intra- A total of 11 men were enrolled between April 2004 venously twice daily, concomitantly with 1,500 ml of and January 2005. One patient discontinued foscarnet normal saline, and calcium and phosphorus supple- at week 2 because of toxicity. The remaining 10 mentation. This fixed dose corresponds to a median patients were assessable at W6. weight-based dose of 85 mg/kg twice daily on the basis The median age of the 11 patients was 49 years of median weight of French HIV-infected patients with (range: 33–75). All had been extensively treated, end-stage disease. Patients were hospitalized for a having been exposed to a median of 14 antiretroviral minimum of 10 days in order to assess tolerability. drugs (range: 11–16), including enfuvirtide (8/11) and The only permitted changes in antiretroviral tipranavir (7/11), over a median period of 12 years therapy were the addition of zidovudine (AZT; (range: 4.5–13.2).

300 mg twice daily) if AZT was not included in the The median baseline pVL was 5.18 log10 copies/ml baseline regimen (or the addition of stavudine [d4T] (range: 4.72–6.66) and the median baseline CD4+ T-cell 30 mg twice daily in case of AZT intolerance), and count was 10/mm3 (range: 1–49). Ongoing antiretro- tenofovir discontinuation in order to avoid viral therapy at baseline is shown in Table 1. Eight potential additive nephrotoxicity. Induction therapy patients started AZT and one d4T concomitantly with lasted 6 weeks. foscarnet; the remaining two were already on AZT in

Patients who had at least a 1 log10 fall in pVL at W6 their background regimen. were offered MT, consisting of foscarnet 5 g intra- All the patients had experienced AIDS-defining venously twice daily on two consecutive days per week. events, and nine patients had at least one active oppor- Ongoing antiretroviral therapy could be optimized tunistic infection at baseline, consisting of oesophageal before starting MT. candidiasis (n=3), disseminated Mycobacterium avium- intracellulare complex (MAIC) infection (n=2), Clinical and laboratory evaluations lymphoma, CMV retinitis, HIV encephalitis, chronic The patients had weekly clinical examinations and diarrhoea and cryptosporidiosis (one case each). The efficacy and safety assessments (biochemistry, viral median body weight was 65 kg (range: 56–74). Median load assay and CD4+ T-cell count). Plasma HIV-RNA creatinine clearance was 80 ml/min (range: 60–100) was quantified with the Amplicor Monitor assay and median haemoglobin was 9.8 g/dl (range: (v1.5; Roche Diagnostics, Meylan, France) which 8.1–13.3); 5/11 patients (45%) had grade 1 anaemia. has a detection limit of 200 copies/ml. The RT gene As shown in Table 2, all the patients harboured was sequenced (codons 1–240) by means of auto- highly mutated viruses, with a median of 24 resistance mated population-based full-sequence analysis (ABI mutations (range: 18–28), including nine associated 3100 Genetic Analyser, PE Applied Biosystems, with NRTI resistance (including four TAMs), two asso- Foster City, CA, USA) at baseline, at the end of ciated with NNRTI resistance and 12 associated with induction therapy, and monthly during maintenance PI resistance. Five patients had mutations associated therapy. All mutations in the RT and protease genes with enfuvirtide resistance. Four patients had resistance leading to amino acid changes were analysed, mutations reported to influence foscarnet susceptibility including mutations probably linked to foscarnet (K65R in patient 1, H208Y in patient 6, L228R in resistance [8,9,15]. patient 10, and H208Y in patient 11).

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 log10 CD4 HIV-RNA ∆ VL log10 treatment cells/ HIV-RNA cells/ copies/ from Background ARV Reason for cells/ copies/ from Patients at baseline* mm3 copies/ml mm3 ml baseline optimization Time discontinuation mm3 ml baseline

1 TZV 4 195,000 26 2,240 –1.94 TZV/ATZr/T20* W4 Failure 73 80,800 –0.38 2 TZV/TPVr/T20‡ 54 153,000 70 < 200 – 2.88 AZT switched W33 TMC-114 100 3,730 –1.61 to d4T 3 TZV/TPV/SQV/ 10 105,000 15 134,000 –0.11 — — TMC-114 — — — LPVr 4 TZV/ddI/TPV/ 14 52,500 98 1,220 –1.63 TZV/ddI/ATZ/ W29 TMC-114 176 5,950 –0.95 SQV/LPVr/T20‡ APVr/T20* 5 ABC/d4T/3TC/ 2 106,000 Stop at W2 for oedema — — — — — — TPVr/T20‡ 6 TZV-TPV 12 129,000 47 736 –2.24 T20* W24 TMC-114 83 3,60 –2.55 7 CBV/IDVr 5 150,000 8 3,500 –1.63 3TC/d4T/TPV/ W12 Failure 17 84,900 –0.25 APVr/T20* 8 CBV/APVr 6 138,000 53 <200 –2.84 CBV/LPV/APV/ W14 Failure 29 25,900 –0.73 T20* 9 TZV/APV/ATZ/ 1 4,580,000 1 246,000 –1.27 — — TMC-114 — — — SQVr/T20‡ 10 TZV/ddI/APVr 24 450,000 133 605 –2.95 — — TMC-114 — — — 11 TZV/APV/ATZ/ 15 564,000 126 65,000 –0.94 — — 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 foscarnet because of virological failure: patient 1 during induction therapy after 4 weeks and patient 7 after 12 weeks. The

Eight patients had at least a 1-log10 reduction in pVL at median change in pVL after 12 weeks of MT was

W6 (8/11, 73% in the intent-to-treat analysis; 8/10, –0.85 log10 copies/ml (n=4) (range: 0.04 to –2.81), 80% in the on-treatment analysis). and the median change in the CD4+ T-cell count was The median change in HIV RNA from baseline was +60 cells/mm3 (range: 12–137). At 24 weeks, three

–1.39 log10 copies/ml (range: –0.45 to –2.39) at W1, patients had received MT and had sustained pVL

–1.99 log10 copies/ml (range: –0.50 to –2.49) at W2, below 5,000 copies/ml.

–1.82 log10 copies/ml (range: –1.02 to –2.88) at W4, and –1.79 log10 copies/ml (range: –2.88 to +0.11) at Changes in genotypic resistance W6 (Figure 1). No change in baseline mutations associated with NRTI The median increase in the CD4+ T-cell count was or PI resistance was observed during either induction 28/mm3 (range: 0–111) at W6. Five patients (50%) or maintenance therapy. who received the full induction course had CD4+ T-cell One patient (2) had selected the K219R foscarnet counts above 50/mm3 at W6. mutation at the end of induction phase (W6; Table 2). Two patients (4 and 6) also harboured virus with this Maintenance therapy mutation at W16 and W24 of MT, respectively. Despite

Of the eight patients who had at least a 1 log10 reduc- this, these three patients had virological response at the tion in pVL at W6, six started foscarnet maintenance moment of resistance emergence (–2.88, –0.77 and therapy, and the remaining two patients were –2.55 log10) and during the study (Table 1). No other enrolled in a Phase II trial of a new antiretroviral change was observed on the RT gene sequences in the agent. Of these six patients, two discontinued 11 patients.

Antiviral Therapy 11:5 563 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, L33F, G48M, V82A, I84V, L90M None G36D (W6) H208Y – V118I, M184V, L210W, T215Y, K219N

*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 3 days after foscarnet discontinuation. One patient Only one patient discontinued foscarnet during the had an infection associated with an intravenous induction phase (W2), because of oedema with renal device, which resolved on antimicrobial impairment and proteinuria; renal function recovered chemotherapy. No cases of renal impairment occurred during MT. AZT was discontinued in three patients for anaemia during induction phase (two Figure 1. Changes in HIV plasma VL during the 6-week- grade 1 and one grade 2); they were switched to d4T. induction phase Median haemoglobin was 9.0 g/dl (range: 7.0–10.7) at W6 and 7/11 patients (64%) had anaemia less than 0 or equal to grade 2. One patient experienced genital -0.5 ulceration that improved with local hygiene and treatment. -1 -1.39 -1.5 -1.99 -1.82 -1.82 -1.86 -1.79 Clinical events and follow-up -2 No new AIDS-defining events occurred during the -2.5 study period. Four patients had a clinical improve- ment in ongoing AIDS-related disorders (HIV -3 encephalitis, cryptosporidiosis, CMV retinitis and -3.5 severe chronic diarrhoea). W1 W2 W3 W4 W5 W6 Two patients (5 and 9) died of progressive HIV n 11 11 10 10 10 10 disease, 2 and 3 months after foscarnet VL, viral load; W, week. discontinuation.

Discussion Several strategies had been evaluated to significantly reduce viral replication in patients with multi-resistant In this pilot study of foscarnet therapy in HIV-infected viruses. Short-term treatment interruption followed by patients with virological failure after exposure to at ‘gigatherapy’, including at least one active drug to least three classes of antiretroviral drugs, pVL fell by a which the patient has never been exposed, is associated median of –1.79 log10 copies/ml after 6 weeks of treat- with a virological benefit [16], whereas a 12-week ment, and the CD4+ T-cell count rose by a median of treatment interruption failed to restore the antiviral 28/mm3. All patients had a sharp decline in pVL at W2, efficacy of salvage gigatherapy comprising only previ- which was maintained at W6 in 9/10 patients. ously used drugs, and was clinically deleterious As foscarnet was added to a failing antretroviral [17–20]. By now, the best option for heavily treated regimen, it is very likely that the observed virological patients is a regimen containing at least two active efficacy was due to foscarnet itself. Viral resistance was agents [1,2], but this is not always possible. probably the main reason for virological failure at Although our findings need to be confirmed in larger study entry, as the patients had adequate drug concen- studies, they suggest that foscarnet might allow trations (not shown) but a median of 21 resistance- patients with very advanced HIV disease and no other associated mutations (range: 16–25). treatment option to survive until new active therapies Similar results have been reported by Mathiesen et al. become available. [14], who gave foscarnet salvage therapy to seven patients and observed a fall in pVL of –1.8 log10 after 2 weeks. References The precise mechanism of foscarnet action is 1. Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvir- unclear. 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