Over a third of patients who take once-daily ritonavir-boosted saquinavir with the anti-tuberculosis drug, rifampicin, have blood levels of saquinavir which are too low to effectively fight HIV, according to a study published in the November 1st edition of the Journal of Acquired Immune Deficiency Syndromes. The study’s Spanish investigators conclude that their findings show that a 1600/200mg once-daily dose of saquinavir/ritonavir cannot be recommended for individuals who are taking anti-tuberculosis therapy containing rifampicin at the same time.
Tuberculosis is the most common AIDS-defining illness worldwide and unlike other AIDS-defining illnesses, it can occur when an individual has a relatively intact immune system. There is also some evidence that potent anti-HIV treatment has not led to the same decline in the number of new tuberculosis cases as seen with other AIDS-defining infections.
Rifampicin is an essential drug for the treatment of tuberculosis. It is metabolised by the body using the P450 enzyme, which is also used by protease inhibitors, and it is known that rifampicin can reduce blood levels of “unboosted” protease inhibitors, such as saquinavir, indinavir, nelfinavir and amprenavir by over 80%. Even though rifampicin does not affect blood levels of full dose ritonavir, it brings other problems particularly a high rate of side-effects.
A small dose of ritonavir is now widely used to boost blood levels of many protease inhibitors, and the investigators wished to see what the effect of rifampicin was on ritonavir-boosted saquinavir. The study was designed to last for 48 weeks and the outcomes were the proportion of patients with a viral load below 50 copies/ml, the number of patients who experienced virological failure, and the percentage of patients who had adequate blood levels of boosted saquinavir.
The study involved 32 patients who were HIV-positive and had tuberculosis. They were prescribed tuberculosis therapy consisting of three or four drugs including rifampicin for two months; they then switched to a two-drug treatment regimen consisting of rifampicin and isoniazid. After two months they also started once-daily anti-HIV treatment consisting of ddI (400mg if over 60kg, 250kg is below), 3TC (300mg) and saquinavir boosted by ritonavir (1600mg/200mg).
Before anti-tuberculosis treatment was started, patients had a median viral load of just over 100,000 copies/ml and a median CD4 cell count of 111 cells/mm3.
Using a rigorous intent-to-treat analysis, the investigators found that after 48 weeks of anti-HIV therapy, 20 patients (63%) had a viral load below 50 copies/ml. Of the 28 patients still on anti-HIV treatment at this time 71% had an undetectable viral load. The median increase in CD4 cell count was 138 cells/mm3.
Virological failure occurred in six patients. Genotypic testing was conducted on blood samples obtained from five individuals and indicated that all have the M184V mutation which confers resistance to 3TC and three had the L90M mutation which is associated with resistance to saquinavir.
Blood levels of saquinavir were studied in 28 patients. In ten of these individuals, trough levels of saquinavir were below the minimum concentration needed to fight HIV. Overall, the median concentration of saquinavir was 44% lower than would be expected if the patients had not been taking rifampicin.
Anti-tuberculosis therapy was effective in all but one patient, and the most commonly reported side-effect of anti-HIV treatment was mild diarrhoea, reported by 41% of individuals. However, two patients had to stop antiretroviral therapy because of acute hepatitis.
“The present exploratory study shows that the combination of ddI, 3TC, saquinavir, and ritonavir may provide a useful, safe regimen for HIV-infected patients with tuberculosis, in whom a once-daily protease inhibitor containing regimen is indicated,” write the investigators. However, they stress that the trough concentrations of saquinavir seen in their study mean that “the 1600/200mg dose of saquinavir/ritonavir cannot be recommended.”
They conclude, “it is necessary to assess higher doses of saquinavir (e.g. 2000mg) boosted with ritonavir, in comparison with the standard saquinavir/ritonavir regimen (1000mg/100mg twice-daily) to achieve a more favorable pharmacokinetic profile and further increase therapeutic efficacy.”
Ribera E et al. Once-daily regimen of saquinavir, ritonavir, didanosine and lamivudine in HIV-1 infected patients with standard tuberculosis therapy (TBQD study). J Acquir Immune Defic Syndr 40: 317 – 322, 2005.