Effectiveness of Low-Dose Indinavir/Ritonavir at 400/100 mg Twice a Day With 2 Nucleoside Reverse Transcriptase Inhibitors in Nonnucleoside Reverse Transcriptase Inhibitor-Experienced HIV-Infected Patients in India

To the Editor: There are an estimated 5 million HIV-infected people in India. The nonnucleoside reverse transcriptase inhibitor (NNRTI)-based combination antiretroviral therapy (cART) is the first-line therapy for HIV-infected patients in India and in the developing world. And, unlike in developed countries, there are limited options available for patients who failed on first-line cART in developing countries. Low-dose indinavir (IDV)/ritonavir at 400/100 mg BID with 2 nucleoside reverse transcriptase inhibitors (NRTIs) is the most cost-effective boosted protease inhibitor (PI)-based regimen in India; therefore, it deserves a study. Indinavir as cART at standard dosages (800 mg TID) had proven efficacy and benefits.1 Unboosted IDV has been replaced by ritonavir-boosted IDV (IDV/r) because of the complex dosing schedule, food interaction, and toxicities related to unfavorable pharmacokinetics.2-4 Ritonavir at 100 mg BID along with IDV improves the pharmacokinetics of IDV and allows dose reduction and convenient twice-a-day administration without dietary restrictions.5,6 The IDV/r at 800/100 mg BID is associated with similar virologic response as compared with 800 mg TID but with significant increased toxicity, with a discontinuation rate for IDV/r at 800/100 mg BID of 20% to 47% for adverse events and 19% to 33% for nephrolithiasis.5-7 This has been related to very high Cmax level achieved with these regimens.8 Few small studies have shown that IDV/r at the lower dosage of 400/100 mg BID may offer the advantage of lower IDV Cmax and significantly improve or maintain the Cmin. This is associated with reduced toxicity with improved compliance and tolerability.8-10 Some pharmacologic, clinical, immunologic, and virologic data are now available with IDV/r at 400/100 mg BID in antiretroviral therapy (ART)-naive patients, but data are still sparse in ART-experienced patients. We described the effectiveness of low-dose IDV/r along with 2 NRTI in NNRTI-experienced patients. We conducted an observational longitudinal cohort study conducted at Infectious Diseases Clinic, a tertiary care private HIV clinic in Ahmadabad, India. The NNRTI-based cART-experienced (nevirapine [NVP] or efavirenz [EFV]) HIV-infected patients were started on IDV/r at 400/100 mg BID with 2 NRTIs. Nonnucleoside reverse transcriptase inhibitor failure was defined as immunologic and/or virologic failure, as per Department of Health and Human Services guideline. Patients with a minimum of 3 months of follow-up were included in the analysis. Baseline demographic and clinical data were collected. Response to treatment was assessed using clinical (no evidence of disease progression), immunologic (serial rise in CD4 cells), and virologic (undetectable viral load [<400 copies/mL] or more than 1 log reduction in viral load at week 12) parameters. Generic antiretroviral drugs manufactured by Indian pharmaceutical companies were used. Nucleoside reverse transcriptase inhibitor combinations were selected by the treating physician depending upon previous nucleoside exposure, availability, and affordability. Patients were followed up clinically every month or more frequently until clinical and immunologic stabilization and then every 3 months. Patients were examined in detail to find out opportunistic infection and various adverse effects related to medications at each visit. Adverse events were defined as any event judged by the investigator to be definitely, probably, or possibly related to the administered drug. Adherence was assessed by self-reporting. CD4 cell counts (FACScount, Becton Dickinson, Haryana, India) were measured in all the patients at baseline and every 3 months. Plasma viral load (pVL; Roche Cobas Amplicor, version 1.5; Roche Diagnostics, Mumbai, India) was measured only in patients who could afford it. Viral load was done at baseline and/or after 12 weeks of therapy. Resistance assays were not done. Age and weight data were analyzed. Immunologic and virologic data for the 12-month period were collected and analyzed. To assess change in CD4 from baseline at every 3 months, a paired t test was used. Statistical analysis was carried out using GB Stat, version 7.0 (Dynamic Microsystems, Inc, MD). RESULTS Baseline characteristics of 133 patients included in the study are shown in Table 1. Patients' previous regimens used were d4T + 3TC + NVP (n = 81), AZT + 3TC + NVP (n = 22), d4T + 3TC + EFV (n = 25), and AZT + 3TC + EFV (n = 5). Median duration of follow-up with EFV- and NVP-based cART was 191 months (range, 10-46 months) and 25 months (range, 7-71 months), respectively. The NRTI combinations used in current regimen were d4T + 3TC (n = 52), d4T + ddI (n = 30), AZT + 3TC (n = 26), AZT + ddI (n = 18), 3TC + ddI (n = 5), and 3TC + ABC (n = 2). Median CD4 count at 3, 6, 9, and 12 months were 257 cells/μL (range, 21-619 cells/μL; n = 133), 243 cells/μL (range, 7-881 cells/μL; n = 85), 229 cells/μL (range, 22-1033 cells/μL; n= 50), and 282 cells/μL (range, 80-756 cells/μL; n = 25), respectively, as shown in Figure 1. Rise in CD4 cell count from baseline was significant (P < 0.0001) at each time point.FIGURE 1: Median (range) CD4 cells count at vatious time points.TABLE 1: Baseline Characteristics (N = 133)Virologic response is shown in Table 2. Plasma viral load was carried out at baseline and at 12 weeks in 19 patients. Median baseline pVL was 4.9 log10 copies/mL (range, 3.9-5.9 log10 copies/mL). Median pVL at 12 weeks in patients achieving more than 1 log reduction and failing were 3.4 log10 copies/mL (range, 2.8-4.2 log10 copies/mL) and 5.5 log10 copies/mL (range, 5.5-5.7 log10 copies/mL), respectively. In 17 patients, pVL was done only at 12 weeks to know treatment response. Available virologic data suggest that 22.22% (8/36) of the patients had virologic failure at 12 weeks, and 7.21% (7/97) of the patients had immunologic failure (2 at 24 weeks, 3 at 36 weeks, and 2 at 48 weeks). During the 1-year follow-up period, 11.28% (15/133) of the patients had treatment failure (8 had virologic failure and 7 had immunologic failure); of them, 6 patients were nonadherent (either taking treatment irregularly or had discontinued treatment because of financial constraints). None of the patients under treatment were lost to follow-up, died, or had clinical progression during the follow-up period.TABLE 2: Virologic Response at 12 WeeksAll patients followed up in this study tolerated medications well. None of the patients discontinued medications because of adverse reactions. Adverse reactions were seen in 21.80% (n = 29) of the patients. They were gastrointestinal disturbances (7.51%), retinoidlike effects (10.52%), nephrolithiasis (3.00%), indirect hyperbilirubinemia (1.50%), and hepatitis (1.50%). DISCUSSION The IDV/r regimen of 800/100 mg BID is the best studied regimen and has demonstrated clinical efficacy comparable to that of IDV at 800 mg TID (HIV RNA levels of <50 copies/mL in 64% and 59% of the patients, respectively) in the BID Efficacy and Safety Trial (BEST) study and offers greater potential to overcome resistance with higher maintained levels of drugs in the blood.7,11 Cost is prohibitive for most Indian patients in using IDV/r at 800/100-mg BID doses. In various small studies conducted with IDV/r at 400/100-mg BID dose in ART-naive patients, short-term and long-term virologic response was good, side effects were markedly reduced with improved compliance. Lamotte et al8 showed that IDV/r at 400/100 mg BID was associated with a marked reduction in side effects compared with the 800/100 mg BID dosage. Ghosn et al9 reported that an IDV/r regimen of 400/100 mg BID was effective in maintaining an undetectable viral load for 48 weeks in 20 patients previously receiving IDV at 800 mg TID. Justesen et al,12 in their long-term follow-up study of heterogeneous population of HIV-1-infected patients receiving IDV/r at 400/100 mg BID with 2 NRTI, showed that 70% of the patients had viral load of less than 20 copies/mL after 120 weeks of therapy. Konopnicki et al10 compared IDV/r at 800/100 mg BID and 400/100 mg BID in ART-naive subjects and found similar efficacy with both regimen at 48 weeks, but safety and tolerance were significantly better with 400/100 mg. In all the previously described studies, the study population is either ART-naive or receiving IDV at standard dosage with suppressed pVL. Katlama et al13 demonstrated efficacy of low-dose IDV/r in ART-experienced subjects with viral load of less than 200 copies/mL. To our knowledge, this is the first study evaluating the effectiveness of low-dose IDV/r as a second-line regimen in NNRTI-experienced Indian patients. These are the preliminary results from our study; it requires careful interpretation because we do not have resistance data for selection of nucleoside backbone and viral load measurement for all patients. Many of them (87.21%) have received one or both previously used NRTI. Baseline anemia, expensive abacavir, and nonavailability of tenofovir compelled us to use stavudine. The NNRTI-experienced patients were likely to have resistance to NNRTI and 3TC. We tried to exploit 3TC resistance and continued in second-line regimen because we do not have many options. At the same time, we assumed that all NNRTI-experienced patients were PI naive and probably do not carry resistance to PIs. In our observational study, rise in CD4 count from baseline was significant at each period, from 3 months (P = 0.0001) to 1 year (ie, at 3, 6, 9, and 12 months). At 12 weeks, 61.11% (22/36) of the patients had complete viral suppression (pVL < 400 copies/mL, HIV RNA not detected), 16.66% (6/36) of the patients had greater than 1 log reduction, and 22.22% (8/36) of the patients had virologic failure. Boyd et al14 demonstrated higher IDV exposure with reduced dose of IDV/r (400/100 mg) in ART-naive Thai patients with body weight of less than 55 kg. In our study, patients' median body weight was 54 kg (range, 34-80 kg), and 48.12% of the patients had weight below 55 kg. Incidence of side effects was very low in comparison to other studies, and none of the patients required drug discontinuation. This regimen is effective as second-line therapy in NNRTI-experienced patients, with more convenience, less pill burden (6-7 pills/d), and less drug-related adverse reaction. An additional benefit is a substantial cost reduction that makes treatment more affordable for patients in developing countries such as India. In conclusion, this observational study found that, in the clinical setting, IDV/r at a dose of 400/100 mg BID along with 2 NRTI is effective in achieving viral suppression and CD4 cells improvement during a 1-year follow-up in NNRTI-experienced population. Low-dose IDV/r is cheaper, convenient, safe, and well tolerated. These results need to be confirmed in larger clinical trials with detailed laboratory workup. Coformulation of IDV/r in tablet form can further simplify the treatment regimen without need for refrigeration. ACKNOWLEDGMENTS The authors thank Drs S. Dileep and Nilay Mehta Ahmadabad, from India, for their invaluable help in the preparation of the manuscript. Presented at the Third International AIDS Society Conference on HIV Pathogenesis and Treatment; July 24 to 27, 2005; Rio De Janeiro, Brazil. Oral Poster MoPp. 0306. Atul K. Patel MD* Ketan K. Patel MD* Jagdish K. Patel MD† Rakesh L. Sharma MD* Rajiv R.