-- The penetration of indinavir into the central nervous system and into the male genital tract is enhanced after low-dose ritonavir is added to the drug cocktail, researchers in The Netherlands report.
"Penetration of antiretroviral drugs into anatomical HIV-1 reservoirs such as the male genital tract and the central nervous system is important," wrote R.M.E. van Praag and colleagues from the University of Amsterdam, The Netherlands ("Enhanced penetration of indinavir in cerebrospinal fluid and semen after the addition of low-dose ritonavir," AIDS 2000 Jun 16;14(9):1187-94.
"Data on indinavir (IDV) concentrations in seminal plasma are lacking and IDV concentrations in cerebrospinal fluid are at best borderline."
Thirteen patients were included in the study. The patients started treatment with zidovudine (or stavudine), lamivudine, abacavir, nevirapine, and IDV (1,000 mg three times daily). Eventually, treatment with nevirapine led to low IDV concentrations in the patients. At that point, a change was made where the IDV was given in combination with ritonavir (RTV). The dosage of IDV/RTV was 800/100 mg twice daily in hopes it would improve the pharmacokinetic profile of IDV.
The patients provided blood samples for a serum pharmacokinetic profile, as well as a semen sample and a cerebrospinal fluid sample at weeks 8, 24, 48, and 72.
Test results showed that the addition of RTV increased the median IDV trough concentration in serum from 65 to 336 ng/ml (P=0.005). The researchers observed also that the median IDV concentration in nine patients' seminal plasma increased from 141 to 1,634 ng/ml (P=0.002) and in the cerebrospinal fluid from 39 ng/ml in 12 patients to 104 ng/ml in seven patients (P<0.001).
"In six patients with samples collected both before and after the addition of RTV the IDV concentration in seminal plasma increased 8.2 times [95% confidence interval (CI), 5.2-11.6], and in cerebrospinal fluid 2.4 times (95% CI, 1.8-3.9)," added van Praag et al.
The researchers reported that the IDV was able to better penetrate the male genital tract when the RTV was added.
"The addition of low-dose RTV not only increases IDV concentrations in serum but also in seminal plasma and cerebrospinal fluid, thereby probably improving the potency of the regimen in these anatomical HIV reservoirs," concluded van Praag et al. "Higher serum trough levels alone can not sufficiently explain the observed increases in seminal plasma and cerebrospinal fluid concentrations. Inhibition of P-glycoprotein-mediated transport by RTV might be an additional mechanism."
The contact person for this report is J.M. Prins, University of Amsterdam, Academy Medical Center, Department of Internal Medicine, Division of Infectious Diseases and Tropical Medicine & AIDS, NATEC, Room F4-217, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands.
A search of the www.NewsRx.com online database using the terms "HIV" and "ritonavir" generated 172 articles.
Key points reported in this study are:
- Penetration of indinavir (IDV) into the central nervous system and the male genital tract is important for reducing HIV viral reservoirs in these areas
- Generally, IDV penetration in these areas is borderline
- Low-dose ritonavir added to IDV therapy enhanced penetration of IDV in cerebral spinal fluid and semen of male HIV patients
This article was prepared by AIDS Weekly editors from staff and other reports.