Minimising the number of doses and pills

It has taken nearly five years for companies that are developing antiretrovirals to deliver dosing schedules that are more convenient and flexible than the original three times daily, highly food restricted dosing regimens that characterised the early years of antiretroviral therapy for many patients.

Several studies have shown that once daily regimens are preferred by patients (La Paz 2004) and improve adherence, that regimens with fewer pills improve adherence (Knobel 2004) but that dosing frequency alone may not improve adherence (Stone 2004).

Development is now focusing on a number of avenues to enable simplified dosing of antiretrovirals:

• New formulations that allow once daily dosing without significantly greater frequency of side effects.

• Boosting blood levels of a protease inhibitor by using ritonavir to slow clearance of the drug.

• Co-formulation of drugs into one tablet or capsule.

• Switching to a simpler regimen after viral load has been suppressed with the most potent therapy available (induction and maintenance therapy).

Several single drugs are licensed for once daily use: abacavir (Ziagen), atazanavir (Reyataz), efavirenz (Sustiva), tenofovir (Viread), 3TC (lamivudine, Epivir), FTC (emtricitabine, Emtriva) and ddI (didanosine, Videx / VidexEC). Two once-daily combination tablets were also licensed in 2004: a tenofovir plus FTC tablet (Truvada) and an abacavir plus 3TC tablet (Kivexa), both of which can be taken with or without food. These can be taken alongside the once daily drugs efavirenz and atazanavir to create a once-daily regimen, although tenofovir may reduce atazanavir blood levels if the latter drug is not boosted by ritonavir.

Fosamprenavir (Telzir) can also be dosed once daily with ritonavir according to the United States product license, but European dosing instructions recommend the drug should be taken twice daily. Similarly, a once daily version of ritonavir-boosted lopinavir (Kaletra) is licensed in the United States, but not in Europe.

Simplifying therapy may also involve switching to a simpler twice daily regimen after viral load becomes undetectable on a two or three times daily regimen (usually a protease inhibitor-containing regimen). Switching from PI-based to NNRTI-based combinations may reduce dosing frequency, pill burden and dosing restrictions. One study with two and a half years of follow-up has found the switch from a PI to nevirapine is safe and effective (Gil 2003) while shorter term follow-up shows quality-of-life measures improve with a simpler medication schedule (Munoz 2003).

For people who developed lipid abnormalities while taking PIs, a move to a combination of four NRTIs has also been reported. Two of 19 people experienced viral rebound after changing to AZT, 3TC, abacavir and tenofovir (Ruane 2003). Given that triple NRTI therapy is no longer recommended due to its lack of potency, quadruple NRTI therapy should be regarded as experimental.

Starting with three or four drugs and stepping down to treatment with two or even one drug for longer term maintenance is an experimental strategy attracting renewed interest. Induction and maintenance approaches are discussed in more detail in Induction and maintenance therapy in Anti-HIV therapy: Choosing your treatment strategy.

Drawbacks of once daily therapy

The only major drawback of once daily therapy is the danger that if a dose is missed and a further dose is not taken until 24 hours after the missed dose, plasma levels will have fallen far lower than if one out of two daily doses had been missed. This is likely to be particularly problematic when drugs are used which fail after the development of one mutation - drugs such as 3TC, FTC, efavirenz and nevirapine. However each of these drugs has a long half life and achieves trough levels much higher than the minimum levels needed for successful viral suppression, which means that an occasional 48 hour interval between dosing rather than a 24 hour interval may not be too serious.

Once-daily nucleoside and nucleotide reverse transcriptase inhibitors

At present the only NRTIs / NtRTIs that are approved as once-daily treatments are:

• FTC.

• ddI.

• Tenofovir.

• 3TC.

• Abacavir.

FTC is the latest NRTI to be approved for use in combination with other anti-HIV drugs. A similar drug to 3TC, FTC may be taken once daily by adults and children. ddI is licensed in Europe either in a tablet form or a new capsule form, as a once daily drug. 3TC has also been licensed in Europe as a once daily 300 mg tablet. Tenofovir is now licensed in Europe for as first-line or second-line treatment. Tenofovir has significant interactions with two other antiretrovirals which may be taken once daily - ddI and atazanavir - and is best dosed with food.

A truly once daily regimen appears to be available with FTC, ddI and efavirenz. A study of people randomised to switch to this regimen or continue a PI-based regimen found 95% of switchers maintained a viral load below 50 copies/ml at one year, compared with 87% of those who continued with PI treatment (Molina 2003).

A recent British/Argentinian study compared once versus twice daily abacavir taken with once daily 3TC and efavirenz over 48 weeks. None of the 770 participants had previously taken treatment and 44% had viral loads above 100,000 copies/ml before starting therapy. At 48 weeks, 66% of the once daily abacavir group and 68% of the twice daily group had viral load below 50 copies/ml and CD4 cell rises were about the same. Rates of hypersensitivity were also similar: 10% and 8%, respectively (Gazzard 2003). Due to the large, randomised, double-blind design of this study the findings of this study are highly credible, and suggest that abacavir/3TC/efavirenz once daily is an effective regimen. Further data from a Thai study of once daily abacavir and once daily 3TC showed no difference in rates of virological rebound when compared with a control arm in which both abacavir and 3TC were dosed twice daily.

An extended-release (XR) formulation of d4T has been developed. Data from a randomised 48 week equivalence study in 150 patients showed no difference in viral load suppression after 48 weeks, but a trend towards a lower rate of peripheral neuropathy in the once daily arm (11% vs 1%) (Montaner 2001). A second study also showed a trend towards lower rates of peripheral neuropathy and lactic acidosis (Baril 2002). The once daily formulation of d4T has been formally approved for use by authorities in the US and Europe but is not yet available for prescription due to production delays.

For more details of research into these once daily NRTIs, see specific drug entries in Drugs used by people with HIV: Nucleoside reverse transcriptase inhibitors.

Once-daily protease inhibitors

The new PI atazanavir is now available in the United States and the United Kingdom as a once-daily treatment. Two ritonavir-boosted PIs have also been endorsed as once daily options for first-line PI therapy: saquinavir / ritonavir (1600 / 100mg), which is recommended by current British treatment guidelines, and fosamprenavir / ritonavir (1400 / 200mg), which has been approved by United States authorities. The British guidelines note that many once daily boosted PIs may not be sufficiently powerful to suppress viral load in some patients, due to the risk of lower trough levels and a higher risk of viral breakthrough if the drugs are dosed once daily.

Several studies have supported once daily saquinavir / ritonavir (1600 / 100mg) which involves taking nine capsules. A pharmacokinetic study found that 1600 / 100mg saquinavir / ritonavir resulted in better overall drug exposure over a 24-hour period than three times daily dosing of 1200mg of saquinavir alone, with much higher pre-dosing concentrations (Kilby 2000). The level of gastrointestinal side-effects was increased in the 1600/100mg group. A switch study from Thailand and a comparative study from Peru have reported that once daily saquinavir/ritonavir is as effective as twice and thrice daily saquinavir (Cardiello 2002; Hidalgo 2002). A small observational study in 32 people with advanced HIV disease who had not previously taken treatment showed 75% had viral loads below 50 copies/ml after seven months of treatment, and only two people experienced severe treatment-related diarrhoea (Gonzalez-Garcia 2003).

High rates of gastrointestinal side-effects have been a problem with once daily saquinavir / ritonavir due in part to chemicals present in the soft-gel formulation. As a result, the older formulation of saquinavir called Invirase is recommended when boosted with ritonavir. When combined with ritonavir, the two saquinavir formulations are equally potent, while Invirase is less likely to cause gastrointestinal problems (Kurowski 2002). Furthermore, comparative pharmacological data suggest that Invirase once daily may produce higher concentrations of saquinavir than Fortovase once daily (Cardiello 2002b).

The FOCUS study highlighted the problems with once daily Fortovase / ritonavir. One hundred and sixty-one treatment-naﶥ patients were randomised to receive either efavirenz or soft gel saquinavir (1600mg boosted with 100mg of ritonavir) once daily, together with twice daily nucleoside analogues. Of everyone who started treatment with efavirenz, 71% had viral load below 50 copies/ml at week 48, compared with 51% of those who started saquinavir. This difference was not statistically significant but pointed towards the high number of discontinuations related to side-effects and to the large number of pills in the saquinavir arm of the study. Nearly one third of those randomised to saquinavir/ritonavir stopped their original treatment in the first six months of the study (compared to 20% in the efavirenz arm).

The approval of the once daily PI atazanavir opens up further possibilities for simplified regimens. Studies have suggested that atazanavir does not have the detrimental effect on cholesterol and triglycerides seen with some of the other PIs. Atazanavir is equivalent to efavirenz as a first-line medication but pre-existing PI resistance is likely to reduce the effectiveness of atazanavir. Switching to atazanavir can improve lipid profiles while maintaining undetectable viral load, according to an observational study of 22 people (Markowitz 2003).

Given that prior exposure to PIs undermines the efficacy of atazanavir, boosted atazanavir has been studied in treatment-experienced people. Atazanavir/ritonavir (300/100mg once daily) is equivalent to lopinavir/ritonavir in terms of antiviral potency but it improves blood lipids compared with lopinavir/ritonavir (Badaro 2003). Studies combining atazanavir and saquinavir (400/1200mg once daily) have found this combination to be inferior to lopinavir/ritonavir in terms of antiviral effect but superior to saquinavir/ritonavir (400/400mg) in terms of tolerability and toxicity. Preliminary investigations of once daily atazanavir/amprenavir have also been conducted.

Atazanavir is known to interact with other once daily antiretrovirals such as tenofovir and ddI (Boyd 2003) so dose adjustments or therapeutic drug monitoring may be undertaken. No formal recommendations have yet been made.

Fosamprenavir is a pro-drug of amprenavir, which means that it is converted into amprenavir in the body. As a result, fewer capsules need to be taken. Following studies of once and twice daily fos-amprenavir, with and without ritonavir, American drug regulatory authorities have endorsed fosamprenavir 1400mg once daily (two tablets) with 200mg of ritonavir (2 capsules). Fosamprenavir/ritonavir has not been recommended for once daily dosing in PI-experienced individuals following the findings of the CONTEXT study which compared once-daily fosamprenavir, twice daily fosamprenavir and twice daily lopinavir-ritonavir in 320 people who had previously taken a PI. Fewer of the people taking once daily treatment achieved a viral load below 400 copies/ml compared with people taking twice-daily treatment. However, once-daily fosamprenavir/ritonavir does produce results equivalent to nelfinavir when taken as first-line treatment (Yates 2003; Shurmann 2002). Fosamprenavir alone is not recommended as a once- daily treatment.

Once-daily dosing of standard amprenavir plus ritonavir has also been tested. A dose of 1200mg of amprenavir and 200mg of ritonavir once daily was compared with 600/100mg amprenavir/ritonavir twice daily and 1200mg amprenavir alone twice daily. The once daily dose did not produce a significantly higher peak concentration but total drug exposure after 12 hours was nearly three times greater than amprenavir dosed alone. Twenty-four hours after dosing, the amprenavir concentration was still more than twice as high as the trough concentration produced by standard amprenavir dosing (Wood). There was no significant difference in the rate of lipid abnormalities between the dosing groups in the 39 individuals studied.

Many of the other PIs boosted with low-dose ritonavir have been tested as once daily medications.

Once-daily lopinavir / ritonavir (Kaletra dosed at 800/200mg) has been licensed in the United States, but not Europe. This once daily boosted PI has been compared with standard twice daily dosing in 38 treatment-naive patients also taking d4T and 3TC. After 72 weeks, the proportions with viral load below 50 copies/ml by intent-to-treat analysis were 74% and 58% in the once-daily and twice-daily groups, a non-significant difference. Adverse events, lipid elevations and adherence were unaffected by once-daily dosing (Feinberg 2002).

However, whilst peak lopinavir levels and total lopinavir exposure were similar regardless of dosing regimen, those dosing the drug once a day had lower trough levels than those taking it twice daily. This may not be important for people who take lopinavir/ritonavir as a first-line PI, but it could reduce the benefit to be gained by those with PI resistance, because a lower trough level will mean a lower barrier against emerging resistant virus. It is worth noting that the inhibitory quotient (the ratio of the trough level to the concentration required to inhibit viral replication by 50%, the IC₅₀) in the once daily group was 40, implying a substantial margin of safety.

Although indinavir has been boosted with ritonavir in several studies, dosing has generally been twice daily. Various doses of indinavir and ritonavir have been tested for once-daily dosing (Saah 2001; Mallolas). The most favourable pharmacokinetic profile has been recorded with 1200/400mg, but this was poorly tolerated in healthy volunteers (Hugen). This study was also conducted after a ritonavir induction period to stabilise ritonavir levels and to maximise the inhibition of indinavir metabolism, but this required the use of a 400mg dose. Although the authors of the study suggested that the ritonavir dosage could be reduced to 200mg once indinavir steady state is reached, the tolerability of such an approach for most patients is questionable. A more lengthy pharmacokinetic and efficacy study is clearly needed.

The addition of efavirenz to once daily indinavir/ritonavir results in indinavir trough levels lower than those seen with three times daily dosing, thereby defeating the object of once daily indinavir dosing, and any future use of indinavir/ritonavir with efavirenz is likely to focus on the use of indinavir/ritonavir twice daily (Saah 2001).

The pharmacokinetic studies also found that taking indinavir and ritonavir with food reduced the peak levels of indinavir, and also reduced the number of daily peaks in urinary indinavir concentration. This may theoretically reduce the risk of kidney toxicity, although the total indinavir exposure over a 24-hour period also has a critical influence on the development of nephrolithiasis and related kidney problems.

Once daily nelfinavir/ritonavir has been tested in healthy volunteers. A dose of 2000/200mg was found to be pharmacokinetically viable, but five withdrawals due to adverse events were reported in a group of 27 patients (three due to rash) (Aarnoutse 2003).

Once-daily non-nucleoside reverse transcriptase inhibitors

Efavirenz was the first antiretroviral to be licensed for once daily therapy, so it is a promising component of any once daily regimen, provided that it doesnt interact negatively with any other drug dosed once daily. One study of efavirenz, ddI and 3TC once daily in 75 previously untreated people found 77% had viral load below 50 copies/ml after 48 weeks of treatment (Maggiolo 2001).

Nevirapine has been tested as a component of a once-daily regimen. The international 2NN study found once daily dosing of nevirapine produced equivalent virological and immunological outcomes to twice daily nevirapine and once daily efavirenz (Van Leth 2003). All regimens in this study included d4T and 3TC. The downside of once daily nevirapine was a greater risk of liver toxicity.

Combining efavirenz and nevirapine in a once daily regimen has also been tested (Jordan; Van Leth). In one study, 26 individuals received efavirenz/nevirapine plus ddI once daily. After nine months 25 out of 26 had viral load below 25 copies (with one viral rebound due to a deliberate treatment interruption). Mean viral load at baseline was 33,000 copies/ml (Jordan). However, the larger 2NN study found once daily efavirenz/nevirapine plus NRTIs was associated with a higher rate of toxicity and poorer outcomes.

Other simplified regimens

Simplification can also consist of switching from a protease inhibitor-containing regimen, involving many pills or difficult dosing requirements, to a NNRTI-containing regimen which is easier to take. For example, the DPC-049 study looked at the effect of switching from a PI to efavirenz-containing regimen in people who had taken a PI-containing regimen for an average of 21 months prior to their switch. After 48 weeks on the new regimen, PI recipients were more likely to have experienced viral load rebound (15% vs 7%) or to have discontinued the treatment to which they were assigned (18% vs 11%) (Rachlis).

Another observational report found 78% of 74 people who switched from a PI to nevirapine or efavirenz maintained viral suppression six months after the switch. Those who had previously taken nucleoside mono or dual therapy had lower rates of suppression after switching. Significant improvements in medication adherence were reported (Moya 2003).

Several studies have explored the efficacy of NRTI-sparing regimens with a boosted PI and an NNRTI in treatment-experienced and treatment-naive people (Boyd 2003). See What to start with in Choosing a combination for more details.

References

Aarnoutse R et al. Pharmacokinetics, food intake requirements and tolerability of once-daily combinations of nelfinavir and low-dose ritonavir in healthy volunteers. Br J Clin Pharmacol 55: 115-125, 2003.

Badaro R et al. Efficacy and safety of atazanavir with ritonavir or saquinavir versus lopinavir/ritonavir in combination with tenofovir and one NRTI in patients who have experienced virologic failure to multiple HAART regimens. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 118, 2003.

Baril JG et al. Stavudine extended/prolonged release (XR/PRC) vs stavudine immediate release (IR) in combination with lamivudine and efavirenz: 48 week efficacy and safety. 14th International AIDS Conference, Barcelona, abstract TuOrB1189, 2002.

Boyd M et al. Indinavir/ritonavir 800/100 mg bid and efavirenz 600 mg qd provides durable salvage for patients with combination nucleoside analogue failure: HIV-NAT 009 72 week follow-up. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 581, 2003.

Cardiello P et al. Simplifying protease inhibitor therapy with once-daily dosing of saquinavir soft-gelatin capsules/ritonavir (1600/100 mg): HIVNAT 001.3 study. J Acquir Immune Defic Syndr 29: 464-470, 2002a.

Cardiello P et al. Pharmacokinetics of once-daily saquinavir hard gel caps and saquinavir soft gel caps boosted with ritonavir in HIV-1+ Thai patients. Fourteenth International AIDS Conference, Barcelona, abstract MoPpB2007, 2002b.

Feinberg J et al. Once daily versus twice daily Kaletra (lopinavir/ritonavir) in antiretroviral-naﶥ HIV+ patients: 72 week follow-up. Fourteenth International AIDS Conference, Barcelona, abstract TuPeB4445, 2002.

Gathe J et al. Antiviral activity of enteric-coated didanosine, stavudine, and nelfinavir versus zidovudine plus lamivudine and nelfinavir. Journal of Acquired Immune Deficiency Syndromes 31(4): 399-403, 2002.

Gazzard BG et al. Abacavir (ABC) once daily (OAD) plus lamivudine (3TC) OAD in combination with efavirenz OAD is well-tolerated and effective in the treatment of antiretroviral therapy (ART) naive adults with HIV-1 infection (ZODIAC study; CN30021). 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract LB H-1722b, 2003.

Gil P et al. Long-term efficacy and safety of protease inhibitor switching to nevirapine in HIV patients with undetectable viral load. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 590, 2003.

Gonzalez-Garcia J et al. Saquinavir 1600 mg/ritonavir 100 mg qd plus two nucleosides in HIV+ naive patients (preliminary results). Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 565, 2003.

Haas D et al. Once daily atazanavir plus saquinavir favorably affects total cholesterol (TC) and fasting triglyceride (TG) profiles in patients failing prior PI therapy (Trial AI424-009, Wk 24). 41st Interscience Conference on Antimicrobial and Antiviral Chemotherapy, Chicago, abstract LB-16, 2001.

Hugen PWH et al. Dose finding study of a once daily indinavir/ritonavir regimen. Journal of AIDS 25: 236-245, 2000.

Jordan WC et al. Nevirapine (NVP)+efavirenz (EFV)+didanosine (ddI): a very simple, safe, and effective once-daily regimen. Thirteenth International AIDS Conference, Durban, abstract B3207, 2000.

Kaul S et al. Pharmacokinetic evaluation of the combination of atazanavir (ATV), enteric coated didanosine (ddI-EC), and tenofovir disoproxil fumarate (TDF) for a once-daily antiretroviral regimen. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract A-1616, 2003.

Kilby JM et al. Safety and pharmacokinetics of once-daily regimens of soft-gel capsule saquinavir plus minidose ritonavir in human immunodeficiency virus-negative adults. Antimicrobial Agents Chemotherapy 44(10): 2672-2678, 2000.

Knobel H et al. Impact of simplification to a lower pill burden HAART in adherence and risk factors for non-adherence. XV International AIDS Conference, Bangkok, abstract WePeB5773, 2004.

Kurowski M et al. Comparative pharmacokinetics and short-term safety of twice daily (BID) Fortovase/ritonavir and Invirase/ritonavir. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 432, 2002.

La Paz, H et al. Adherence, treatment-satisfaction and effectiveness of once-daily versus twice-daily antiretroviral therapy in a large prospective observational cohort (CUVA Study). XV International AIDS Conference, Bangkok, abstract WePeB5780, 2004.

Maggiolo F et al. Virological and immunological responses to a once-a-day antiretroviral regimen with didanosine, lamivudine and efavirenz. Antiviral Therapy 6(4): 249-253, 2001.

Mallolas J et al. Dose finding study of once daily indinavir/ritonavir plus zidovudine and lamivudine in HIV-infected patients. Journal of AIDS 25: 229-235, 2000.

Markowitz M et al. 48-week results of an atazanavir-based QD regimen in patients switching from BID PI-based HAART. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 543, 2003.

Molina JM et al. Emtricitabine, didanosine and efavirenz once daily versus continued PI based HAART in HIV-infected adults with undetectable plasma HIV-RNA: 48 week results of a prospective randomized multicenter trial (ALIZE-ANRS 099). Antiviral Therapy 8 (Suppl 1), S193 (abstract 37), 2003.

Montaner JG et al. FOCUS Study: Saquinavir QD regimen versus efavirenz QD regimen 24 week analysis in HIV infected patients. 41st Interscience Conference on Antiviral and Antimicrobial Chemotherapy, Chicago, abstract 670, 2001.

Moya J et al. Efficacy and safety of a once daily regimen with NNRTIs after a successful protease inhibitor-containing regimen. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 591, 2003.

Munoz JA et al. Impact of two simplified therapies with 3 nucs and 2 nucs plus NNRTI, on quality of life and adherence in HIV-1+ infected patients with undetectable viral load. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 592, 2003.

Rachlis A et al. Successful substitution of protease inhibitors with efavirenz (EFV) in patients with undetectable viral loads - a prospective, randomized, multicenter, open-label study (DMP 049). First International AIDS Society Conference on HIV Pathogenesis and Treatment, Buenos Aires, abstract 418, 2001.

Ruane P et al. Efficacy of Trizivir (TZV) and tenofovir (TDF) as HAART for HIV infected patients with current or underlying reverse transcriptase (RT) resistance. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 593, 2003.

Saah A et al. Pharmacokinetic profile and tolerability of indinavir-ritonavir combinations in healthy volunteers. Antimicrobial Agents and Chemotherapy 45(10): 2710-2715, 2001.

Sension M et al. Lamivudine 300 mg QD versus continued lamivudine 150 mg BID with stavudine and a protease inhibitor in suppressed patients. HIV Clinical Trials 3(5): 361-370, 2002.

Stone VE et al. Perspectives on adherence and simplicity for HIV-infected patients on antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes 36: 808-816, 2004.

Shurmann D et al. Efficacy and safety of GW433908/ritonavir once daily in therapy-naive subjects, 48 weeks results: The SOLO study. Sixth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract PL14.4, 2002.

Wood R et al. Enhancement of pharmacokinetic parameters of amprenavir when combined with low dose ritonavir (APV 600mg/RTV 100mg BID) and preliminary efficacy results. Fifth International Congress of Drug Therapy in HIV Infection, Glasgow, abstract P283, AIDS 14 (supp4): S98, 2000.

Van Leth F et al. Results of the 2NN study: a randomized comparative trial of first-line antiretroviral therapy with regimens containing either nevirapine alone, efavirenz alone or both drugs combined together with stavudine and lamivudine. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 176, 2003.

Yates P et al. Optimising 908/r in PI-experienced patients: a retrospective analysis of virological response based on baseline genotype after 8 weeks of therapy. XII International HIV Drug Resistance Workshop, abstract 154, 2003.

Yuen GJ et al. Equivalence of plasma and intracellular triphosphate lamivudine pharmacokinetics (PK) following lamivudine (3TC) 300mg once daily compared to lamivudine 150mg twice daily in healthy volunteers. Fifth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P269, AIDS 14 (supp4): S93, 2000.