Loviride is a non-nucleoside reverse transcriptase inhibitor the family of anti-HIV drugs to which efavirenz and nevirapine also belong. These drugs act by inhibiting HIV's reverse transcriptase enzyme, but in a different way from the nucleoside analogue drugs like AZT, ddC and ddI.

Loviride belongs to the TIBOL class of drugs. TIBOL stands for `TIBO-like compound'. TIBO is an abbreviated form of the chemical name tetrahydroimidazobenzodiazepine, a class of drugs similar to valium. These compounds are also known as alpha-anilino phenylacetamide (alpha-APA) derivatives. Other TIBO/TIBOL compounds that have been studied but are no longer being pursued are R 18893 and R 82913.

Loviride is also known by the codename R 89439 or the brand-name Lotrine. It is manufactured by Janssen Pharmaceuticals.

Current use

Loviride's development has been discontinued following disappointing results in clinical trials.

The CAESAR trial studied the effects of adding 3TC alone, or both 3TC and loviride, to other anti-HIV drugs. Its results, reported in detail in the entry of 3TC, showed that the addition of 3TC alone or both drugs significantly reduced disease progression and death, without any additional side-effects. There was no evidence that people who added both 3TC and loviride experienced better responses than those who added 3TC alone. For more details, see the entry on 3TC.

A study in London and Belgium enrolled people with CD4 counts between 200 and 500 who had use AZT for at least six months. They were randomly assigned to take either loviride alone, AZT alone, AZT plus loviride in combination, or only a placebo for three months followed by three months of loviride alone. Neither loviride alone or AZT alone had a significant effect on recipients' CD4 counts or their viral load. However, combination recipients had a significant and long-lasting increase in their CD4 count. Side-effects of diarrhoea, headaches and nausea occurred in almost everyone, but these had usually stopped after the first 2 months. No strains of HIV with the genetic mutations associated with reduced sensitivity to loviride developed even among those taking the combination for up to two years.

The AVANTI 1 trial among previously untreated people with CD4 counts between 150 and 500 concluded that those treated with AZT/3TC/loviride had a greater fall in viral load and increase in CD4 count than those receiving AZT/3TC alone.

In Phase I trials of loviride 10% of participants experienced diarrhoea. The rash sometimes reported with loviride treatment is a side-effect common to all NNRTIs currently in use, and often disappears if treatment is ceased and does not recur when treatment is re-commenced.

Resistance

There is some evidence to suggest that there is considerable cross-resistance between loviride and the other non-nucleoside reverse transcriptase inhibitors. Research indicates that a search for known NNRTI mutations may not be an effective way of predicting whether or not a person will benefit from loviride.

Key research

Staszewski (1996a) enrolled 114 people with CD4 counts above 400 in a study comparing loviride, R 18893 and placebo. In the loviride group the mean CD4 count increased and remained above baseline until week 24, whereas it fluctuated around baseline for the other two arms. In a subset of participants, viral load at weeks 4, 8 and 12 remained unchanged among placebo recipients, whereas a median decrease of 52% at week 4, 19% at week 8 and 18% at week 12 was observed among loviride recipients. Side-effects included itching and rash involving the elbows and hands, although loviride recipients reported only two cases that were mild.

Youle enrolled 56 non-AIDS patients with CD4 counts between 200-500 and 6-12 months prior use of AZT in a 6 month study comparing loviride alone, AZT alone, AZT plus loviride, and placebo with switch to loviride at 3 months. At the end of the study period 48 participants continued on long-term treatment with AZT plus loviride for up to 2 years. Combination recipients experienced a significant and long-lasting increase in CD4 count.

Staszewski (1996b) compared the triple combination of AZT (200 mg three times daily), 3TC (300 mg twice daily) and loviride (100 mg three times daily) versus the double combination of AZT and loviride (n=10 per arm). No serious drug-induced safety abnormalities or clinically relevant pharmacokinetic interactions were observed. At least half of the triple combination arm experienced CD4 count increases of 78% by week 12, which decreased to 45% after six months. At least half of the dual combination arm had CD4 count increases of roughly 25% by week 4, which had returned to baseline by six months. Initially viral load was strongly suppressed in all patients but began to rebound after 8 weeks and remained below baseline at six months in the triple combination arm, but returned to baseline in the double combination arm.

Rozenbaum enrolled 100 antiretroviral-naive people with CD4 counts between 150 and 500 in the AVANTI 1 trial, comparing AZT/3TC versus AZT/3TC/loviride. Median baseline viral load was 4.8 logs. AT week 52, the median decrease in viral load was 1.3 log in the dual combination arm, and 1.6 log in the triple therapy arm. Median CD4 increases 54.8 and 98.5 respectively. The proportion of participants who achieved viral load below the limit of detection (500 copies/ml) was 11% and 20% respectively.

Kitchen presented results of the QUATTRO trial which enrolled 100 people and randomised them to one of three arms: AZT/3TC/loviride/ddC concurrent therapy; AZT/3TC/loviride/ddC cyclical for 8 weeks; or AZT/3TC. Participants were ART-naive with a mean baseline CD4 count of 181 and a mean baseline viral load of approximately 80,000. At week 64, 28 of 34 in the concurrent arm, 18 of 34 in the cyclical arm, and 28 of 32 in the dual combination arm remained on trial, and the mean viral load reductions were -1.24 log, -0.70 log and -0.78 log respectively. Few mutations to loviride or ddC were found, and mutations associated with 3TC/AZT resistance were less common in the cyclical arm.

Resistance

Miller added loviride to samples taken from people who had previously taken NNRTIs. This study found that genotypic testing did not predict phenotypic response i.e. loviride had little efficacy against HIV if a person had previously taken NNRTIs.

References

Kitchen V et al. A randomised trial comparing regimens of four RT inhibitors given together or cyclically with a standard two drug regimen: the Quattro trial. Fifth Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 701, 1998.

Miller V et al. Patterns of resistance and cross-resistance to HIV type 1 reverse transcriptase inhibitors in patients treated with the nonnucleoside reverse transciptase inihibitor loviride. Antimicrobial Agents and Chemotherapy 42(12):3123-3129, 1998.

Rozenbaum W et al. AVANTI 1. A randomised, double blind, comparative trial to evaluate the efficacy, safety and tolerance of combination antiretroviral regimens for the treatment of HIV-1 infection: AZT/3TC vs. AZT/3TC/loviride in anti-retroviral naive patients. Fourth Conference on Retroviruses and Opportunistic Infections, Washington, abstract 368, 1997.

Staszewski S et al. Evaluation of the efficacy and tolerance of R 018893, R 089439 (loviride) and placebo in asymptomatic HIV-1 infected patients. Antiviral Therapy 1:42-50, 1996a.

Staszewski S et al. Virological and immunological analysis of a triple combination pilot study with loviride, lamivudine and zidovudine in HIV-1 infected patients. AIDS 10(5):F1-F7, 1996b.

Youle M et al. Randomized double-blind trial of loviride (R89439), zidovudine and the combination in HIV-1 infected patients. Second National Conference on Human Retroviruses and Related Infections, Washington, abstract LB6A, 1995.