Short-course Induction with Boosted Saquinavir Monotherapy for Naive Patients with Late-stage Infection

Following is a Research Letter from the current issue of AIDS (January 28, 2005) describing a study that assessed the efficacy of short-course induction treatment with saquinavir/ritonavir as boosted protease inhibitor monotherapy in treatment-naive patients, before switching to conventional HAART:

In South Africa, a high proportion of HIV-1-positive individuals present with symptomatic infection and very low CD4 cell counts (0-150 cells/μl). Conventional HAART including nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) is the most cost-effective option, but may not be initially well tolerated by these patients, as a result of underlying anemia, neutropenia or liver enzyme elevations at baseline. For example, anemia is particularly common among HIV-positive women of African origin, and hemoglobin may be further reduced by zidovudine-based HAART.

Given that saquinavir/ritonavir monotherapy (400/400 mg twice a day) has achieved durable antiretroviral activity in other clinical trials with minimal treatment-emergent PI resistance and that saquinavir with low-dose ritonavir (1000/100 mg twice a day) has shown strong antiviral activity in randomized clinical trials, this study evaluated the use of short-course saquinavir/ritonavir monotherapy, as induction therapy before the use of NRTI/NNRTI-based HAART.

This was a retrospective study of a policy in the centre to treat the most advanced naive patients with boosted PI monotherapy. Twenty-eight consecutive treatment-naive HIV-1-infected adults with CD4 cell counts below 150 cells/μl were assessed. The patients were judged to be too far advanced to tolerate conventional HAART, with low CD4 cell counts, low body weight and evidence of either anemia, neutropenia or liver enzyme elevations.

The antiretroviral treatment used for all patients was saquinavir/ritonavir 600/100 mg twice a day, with the dosage chosen given the low baseline body weight. No other antiretroviral agents were used with the induction PI treatment.

Saquinavir/ritonavir was given for between 4 and 8 weeks, depending on the amount of treatment the patients could afford. At baseline and weeks 4-8, patients were assessed for CD4 cell count, HIV-RNA level (Roche Amplicor 1.5 assay; Roche, Palo Alto, USA), hematology, clinical chemistry, adverse events and HIV disease progression. Changes between baseline and end-of-treatment measurements were analysed using the Wilcoxon signed rank sum test on an intention to treat basis.

Of the 28 patients, 15 (54%) were men and all were of African race. The baseline age was 33 years (range 20-55) with a median body weight of 60 kg (range 33-68), CD4 cell count 26 cells/μl (range 7-110) and HIV-RNA level of 5.5 log₁₀ copies/ml (range 4.6-6.6). The baseline values for hemoglobin (median 11.5 g/dl, range 9-11), neutrophils (median 1.7 × 10⁹/l, range 0.5-6.9) and alanine aminotransferase (median 42 U/l, range 10-133) showed evidence of laboratory abnormalities in a proportion of patients.

All 28 patients completed their initial course of saquinavir/ritonavir monotherapy. There was a median increase in CD4 cell counts of 115 cells/μl, with a reduction in HIV-RNA levels of 2.5 log₁₀ copies/ml after 4-8 weeks of treatment (P < 0.01 for both comparisons). Ten of the 28 patients (36%) achieved HIV-RNA levels below 400 copies/ml after 4-8 weeks of treatment.

Adverse events associated with the saquinavir/ritonavir regimen were bloatedness, diarrhea and asthenia during the first 2 weeks of treatment, which were mild in severity. There were small increases in hemoglobin (median +4%) and neutrophils (median +15%) during the induction treatment, whereas liver enzymes showed reductions (alanine aminotransferase median -23%, aspartate aminotransferase -33%).

Patients were then switched to NRTI/NNRTI-based combinations; NRTI were either zidovudine/lamivudine, or stavudine/lamivudine, given with either nevirapine or efavirenz. After an additional 2 years of follow-up, 26 of the 28 patients are economically active, whereas two have developed disseminated Mycobacterium avium intracellulare infection.

The short-term HIV-RNA reductions and CD4 cell count increases seen in this retrospective study are similar to those observed in a previous pilot study of lopinavir/ritonavir monotherapy, and to those from a randomized trial of saquinavir/ritonavir 1000/100 mg administered twice a day with NRTI, both of which had similar baseline characteristics to this study. First-line HAART often contains two NRTI in combination with a boosted PI; however, the relative antiretroviral effects of the boosted PI versus the NRTI components of this HAART strategy have not been evaluated in randomized trials.

This strategy of boosted PI induction may allow time for an initial recovery of CD4 cell counts with a lower risk of hematological toxicity or liver enzyme elevations, which could otherwise limit the safety of initial treatment with NRTI/NNRTI-based HAART. Liver enzyme elevations have been observed for treatment with higher doses of ritonavir (400 mg twice a day), but have not been an issue for the dosage of 100 mg twice a day used in this study.

The long-term consequences of using boosted PI without other antiretroviral agents are not well understood. Despite the potential safety advantages of sparing NRTI, there is also the potential risk of virological failure or the development of primary PI resistance. New randomized clinical trials are evaluating the efficacy and safety of boosted PI monotherapy relative to conventional NRTI/NNRTI-based HAART for treatment-naive patients.

01/28/05

Reference
O E Osman and A  Hill. Short-course induction with boosted saquinavir monotherapy for naive patients with late-stage infection. AIDS 19(2): 211-212. January 28, 2005.