Efficacy of a Reduced Dose of Darunavir/Ritonavir in a Small Cohort of Antiretroviral-Naïve HIV-Infected Patients

Dear Editor,

D arunavir is a potent protease inhibitor with a high genetic barrier that binds with very high affinity to HIV-1 protease and fits closely within the substrate envelope. ¹ Darunavir 600 mg boosted with low dose ritonavir (100 mg) twice daily is effective and safe in treatment naive and experienced HIV-infected patients. ^{2 –4}

Following the results of POWER trials 1 and 2 ^2,5,6 (performance of TMC114/r when evaluated in treatment-experienced patients with P1 resistance) in treatment–experienced patients with protease inhibitor resistance, darunavir/ritonavir 800/100 mg once daily was selected for naïve patients, and the ARTEMIS trial (antiretroviral therapy with TMC114 examined in naive subjects) confirmed its efficacy. ⁷

However, the results of POWER studies ^5,6 found no correlation between dose of darunavir/ritonavir and efficacy, defined as at least 1 log 10 reduction in HIV RNA from baseline at week 24, for patients with low or no darunavir resistance at baseline (using an exploratory cut-off of fold change <4, recommended by regulatory authorities) (Table 1). We reported previous successful control of viral replication with a reduced dose of darunavir/ritonavir (600/100 mg once daily) in seven antiretroviral treatment-experienced patients with no specific darunavir-resistance mutations. ⁸

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Table 1.

Percentage of Patients With at Least 1 Log 10 Reduction in HIV RNA to Week 24 in the POWER 1 and 2 Trials by Dose Group and Baseline Phenotipic Sensitivity to Darunavir

	Responders
DRV sensitive (fold change <4)
Dose group	n (%)
400/100 mg q.d.	40/51 (78%)
800/100 mg q.d.	39/52 (75%)
400/100 bid	36/43 (84%)
600/100 bid	37/44 (84%)
Control protease inhibitor used	13/50 (26%)
DRV resistant (fold change >4)
Dose group	n (%)
400/100 mg q.d.	16/45 (36%)
800/100 mg q.d.	23/48 (48%)
400/100 bid	31/66 (47%)
600/100 bid	32/54 (59%)
Control protease inhibitor used	14/61 (23%)

In this report, we describe our experience in eleven antiretroviral-naïve consecutive enrolled patients treated with the same dose. Baseline characteristics of the patients, baseline CD4 cell count, baseline plasma HIV-RNA, number of CD4 lymphocytes, and HIV-RNA levels at last visit, and darunavir levels are reported in Table 2.

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Table 2.

Patients' Characteristics, Immuno-Virological, and Pharmacokinetic Data

ID	Age (years)	Sex	CDC class	CD4 lymphocyte at baseline (/μL)	HIV-RNA at baseline (copies/mL)	Months on reduced darunavir dose	Last CD4 cell count (/μL)	Last HIV-RNA level (copies/mL)	Darunavir Ctrough (ng/mL) at 6 months
1	23	F	C3	78	85,501	20	523	<50	2866
2	34	M	A2	308	115,853	19	692	<50	3140
3	35	M	C3	12	334,500	10	208	<50	3627
4	27	M	A2	298	154,000	24	1,380	<50	2553
5	21	M	A2	355	87,330	18	501	<50	3834
6	48	M	A2	215	88,110	19	421	<50	1700
7	42	F	A2	262	34,793	12	401	<50	1268
8	29	F	A2	309	4,526	18	447	<50	3732
9	38	M	A1	536	235,250	20	783	<50	2019
10	27	F	A2	243	7,251	15	507	<50	2818
11	30	F	A2	216	63,244	16	459	<50	4562

The eleven Caucasian patients (five women) had a mean age of 32.8 years (range 21–46) and were not co-infected with hepatitis B or hepatitis C virus. HIV resistance to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, or protease inhibitors was not detected in any of the patients. At baseline, mean CD4 cell count was 193/μL and mean HIV-RNA level was 84,056 copies/mL. Seven patients were co-treated with tenofovir/emtricitabine, and four with abacavir/lamivudine.

Darunavir plasma concentrations were measured 6 months after starting therapy, using a validated HPLC assay ⁹ at the Antiretroviral Drugs' Clinical Pharmacology Laboratory, Amedeo di Savoia Hospital, Turin, Italy. All the patients were taking darunavir in the morning, on a full stomach, and blood was drawn after 24 h from the last dose; the samples were centrifuged at 2500–3000 rpm and plasma was stored at −20°C until tested. After a mean of 17.36 months, plasma HIV-RNA was <50 copies/mL in all patients and the mean CD4 cell count was 574/μL.

For darunavir–ritonavir, an in vivo cutoff value of 550 ng/mL is suggested for treatment-experienced patients; this corresponds to the protein-binding-corrected 50% effective concentration (EC₅₀) for protease inhibitor-resistant strains, and it is used as a reference by therapeutic drug monitoring services. The same target is used for naïve patients with wild-type virus. ¹⁰ Even if there is no correlation between Ctrough and HIV RNA reduction, ^11,12 all our patients had Ctrough values above the protein binding-corrected EC₅₀ value for wild-type virus; the median value was 2866 ng/mL.

In conclusion, our small case series suggests that darunavir/ritonavir once daily at a reduced dose of 600/100 mg could be effective in antiretroviral-naïve patients. However, it is mandatory to perform randomized,double-blind trial to test our hypothesis.