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Antiviral Therapy: How Simple Can You Get?

November 1998

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

The coming of efavirenz and abacavir to market considerably expands the possibilities for simplifying the schedules of antiviral regimes. Efavirenz is taken as three pills once a day whereas abacavir dosing consists of one pill twice a day (see previous article). But these two agents are just the newest of many options developed in the last year to simplify therapies. The increasing experience with the more established antiviral drugs has led to suggested alterations in dosing schedule and treatment strategy that make for less onerous therapies.

Treatment Issues last reported a year ago on ways to alleviate dosing burdens (see Treatment Issues, November 1997). Efforts in this direction have expanded greatly since then, with competitive pressure frequently driving the research. Many simplification strategies were presented at the 12th World AIDS Conference, which took place in Geneva last July, the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) last September in San Diego, and the 4th International Congress on Drug Therapy in HIV Infection this November in Glasgow. These will be summarized below.

Approaches to simplification follow two main lines right now. First is the reduction of thrice-daily (tid) dosing schedules to twice daily (bid) and of twice daily to once daily (qd). The second is the use of therapeutic combinations with a limited number of mechanisms and, one hopes, side effects -- the "protease-sparing" regimens.

There once was a hope that the number of anti-HIV drugs taken could be reduced after a short initial induction period. Trials to test these maintenance therapies have had negative results, with greatly elevated rates of HIV breakthrough. They have waited only three or six months before switching to maintenance, though, and perhaps waiting longer might work better. (For the results of the Dutch ADAM trial see MH Reijers et al. The Lancet, July 1998, pages 185-90; for ACTG 343, see DV Havlir et al. New England Journal of Medicine, Oct. 29, 1998, pages 1261-8; and Treatment Issues, October 1998, pages 6-7; and for the French Trilège study see G Pialoux et al. New England Journal of Medicine, Oct. 29, 1998, pages 1269-76.)

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Trying to reduce the number of medications is no longer a subject of much discussion. Rather, there is a trend toward treatment "intensification," in which antiviral combinations are expanded to include four, five or more antiviral drugs to achieve better success in suppressing HIV. This trend is especially evident in rescue or salvage therapies used to attack HIV that has escaped or not responded to other regimens. It also has been suggested increasingly as necessary to prevent the increasing number of viral rebounds observed as people continue on standard triple-drug therapy (see, for example, Hans Jäger et al. 12th World AIDS Conference, abstract 32319).


Abacavir with or without Combivir

As competition heated up between Glaxo's thrice-daily AZT and Bristol's twice-daily d4T (both nucleoside analogs based on thymidine), Glaxo Wellcome successfully tested and popularized reducing AZT's schedule to 300 mg every 12 hours (see, for example, DH Sheppp et al., Journal of Acquired Immune Deficiency Syndromes, August 1997, pages 283-8). At the same time, Glaxo introduced a 300 mg AZT tablet as an alternative to the old 100 mg capsules. Glaxo then went a step further by combining AZT with its other twice-daily nucleoside analog, 3TC. The result was an AZT/3TC tablet that is taken once every 12 hours and is known as Combivir. Combivir was approved by the FDA in 1997 on the basis of data showing its bioequivalence with AZT and 3TC taken separately.

The price of Combivir is exactly the same as that of AZT plus 3TC. The joint tablet nonetheless gives Glaxo a certain marketing advantage over the alternative combination of d4T/3TC, but does taking one pill twice a day mark any substantial improvement over the twice-daily two-pill schedule that taking d4T/3TC requires?

At the same time, Glaxo's new guanosine-based nucleoside analog, abacavir, might possibly substitute for AZT and 3TC together. The original phase I dose-ranging trial found that abacavir monotherapy caused nearly a 2 log (99%) drop in viral load over four weeks, easily above the range expected for AZT/3TC. In addition, abacavir's resistance pattern is very complicated and again seems equivalent to AZT and 3TC together. Although the same single mutation at the reverse transcriptase gene's codon 184 that is responsible for 3TC resistance does appear in HIV cultured with abacavir, persons whose HIV has only this mutation seem to respond well to abacavir. Abacavir more generally fails in persons with a range of reverse transcriptase mutations, in particular those that give joint resistance to AZT and 3TC (12th World AIDS Conference, abstract 32289).

Last year, a pilot study testing dual combinations of abacavir plus various protease inhibitors found viral suppression comparable to most triple combinations, including AZT/3TC/abacavir, at weeks 4 through 24 (5th Conference on Retroviruses and Opportunistic Infections, abstract 4; also 12th World AIDS Conference, abstract 12213). Preliminary, very incomplete, results from a trial of abacavir combined only with amprenavir, Glaxo's experimental protease inhibitor, indicate that 8 of the first 9 study participants out to 48 weeks had viral loads below 50 copies/ml (12th World AIDS Conference, abstract 12204). All volunteers in these two trials were treatment-naive.

Substituting abacavir for Combivir would not reduce a patient's pill burden but would eliminate the weakly active AZT and its many side effects -- ranging from nausea and malaise to muscle weakness to low white and red blood cell counts. Glaxo Wellcome, though, has chosen to embark on a yearlong study testing AZT/3TC/abacavir against AZT/3TC/indinavir, leaving the potential of the abacavir/indinavir combination unexplored.


From Three Times a Day to Two

The advent of twice-a-day AZT and Combivir triggered a trend toward eliminating tid dosing from antiviral therapy. In developing amprenavir, Glaxo decided upon a thrice-daily schedule although it means that patients will have to swallow eight very large capsules each time. This dosing burden tends to cause gagging and nausea (the latter probably an effect of both the capsules and the drug itself).

Many of the scheduling innovations involve using Abbott Laboratories' protease inhibitor ritonavir to inhibit the metabolism of other protease inhibitors by liver enzymes. This approach was first used to good effect in the combination of ritonavir plus Invirase, the old hard capsule form of saquinavir. Invirase suffered from slow absorption and rapid liver breakdown. Ritonavir bid at 400 mg (four capsules) raised the saquinavir blood levels obtained from Invirase 20 times, in the process converting an almost impotent thrice-daily drug into a highly active twice-a-day one. At the same time, the necessary amount of Invirase was reduced from 600 mg (three capsules) three times a day to 400 mg (two capsules) twice a day. The required ritonavir dose was reduced from 600 mg bid to 400 mg bid, with a concomitant reduction in pill burden and, especially, in ritonavir's notorious side effects (ranging from numbness to elevated blood triglycerides).

Abbott's main trial of the ritonavir/Invirase combination, M96-462, has now followed its initially protease inhibitor-naive volunteers for more than 72 weeks (12th World AIDS Conference, abstract 12295). At this time point, 90% of study participants treated for 72 weeks had viral loads below 200 copies/ml. Especially noteworthy is the fact that most of the volunteers received only the two protease inhibitors without concurrent reverse transcriptase inhibitors at least through the first year.

Abbott is now hoping to repeat this success with indinavir. At the 12th World AIDS Conference (abstract 22361), the company's scientists formally reported earlier observations that ritonavir/indinavir, both dosed at 400 mg bid, resulted in a total exposure to indinavir that was nearly the same as with the standard indinavir dosing schedule, 800 mg three times a day. Peak indinavir levels were reduced while trough levels between doses were increased substantially so that possible windows of opportunity for HIV replication were eliminated. Further, taking the drugs with meals made no difference in indinavir levels whereas indinavir without ritonavir should be taken with, at most, a light snack to achieve proper blood levels.

An uncontrolled pilot study of indinavir/ritonavir, both 400 mg bid, plus two nucleoside analogs was presented at the 4th International Congress on Drug Therapy in HIV Infection by a group of German doctors (abstract P39). The study recruited 71 volunteers with no prior treatment and a median baseline viral load of 210,000. Of the 45 volunteers now followed through week 12, 90% had viral loads below 500 copies/ml, and 75% were below 80 copies/ml. At the 12th World AIDS Conference, four Australian doctors also reported similar dramatic viral load drops with 8 treatment nonresponders and 18 treatment-naive patients on d4T/3TC/ritonavir/indinavir (abstract 22372).

Unfortunately, manufacturing problems have eliminated the supply of ritonavir capsules for the foreseeable future (see Treatment Issues, October 1998), leaving only a vile-tasting liquid formulation as the only ritonavir available. The capsules' disappearance has considerably dissipated last summer's enthusiasm for ritonavir/indinavir. However, a poster at the 12th World AIDS Conference (abstract 42257) suggested a way to alleviate this difficulty. This French study examined reducing the ritonavir dose in a dual protease-inhibitor combination to 100 mg or 200 mg while increasing the saquinavir dose to 600 mg or 1,000 mg and found that saquinavir blood levels again were enormously increased. Not only does reducing the ritonavir dose lessen the noxious taste of liquid ritonavir, but it also reduces the side effects of ritonavir, whether capsule or liquid (nausea and diarrhea, mental confusion, nerve numbness and elevated blood lipids).

At the 4th International Congress on Drug Therapy in HIV Infection, two groups described the use of 100 mg of ritonavir administered twice daily with 800 mg of indinavir (abstracts P38 and P45). Median peak indinavir levels were similar to those achieved with indinavir alone at 800 mg every eight hours while the between-dose minimum levels were four times higher.

Abbott is following a parallel reduced-ritonavir strategy with its new protease inhibitor, ABT-378. Mixing 50 mg to 200 mg of ritonavir with ABT-378 stabilizes the latter at high blood concentrations for over 24 hours. A phase II trial, presented as a late-breaker in Geneva (12th World AIDS Conference, abstract 12460) and in an Abbott-sponsored satellite symposium to the 4th International Congress on Drug Therapy, tested the ABT-378/ritonavir combination at a bid dose of either 200/100 mg or 400/100 mg. After three weeks of dual ABT-378/ritonavir alone, the trial regimen was expanded to include d4T/3TC. The 32 treatment-naive volunteers who started the trial experienced an average 2 log (99%) drop in their viral loads over the first two weeks. Sixteen of 17 volunteers who have been followed through 20 weeks of therapy have viral loads below 400 copies/ml.

For the past year, Merck has been researching twice-daily indinavir without any ritonavir. Merck's favored bid dose for its protease inhibitor was 1,200 mg, compared to the standard 800 mg three times a day. But on September 18, Merck publicly warned against administering indinavir on this twice-daily dosing schedule. Starting a year ago, Merck recruited 635 volunteers without prior treatment to compare AZT/3TC plus either twice-daily or thrice-daily indinavir. Of the 87 participants who reached 24 weeks, 91% on the standard regimen had viral loads under 400 but only 64% on the twice-daily regimen. Twice-a-day indinavir had been controversial because it was feared that the minimum blood levels of drug after 12 hours would be too low to adequately suppress HIV (see Treatment Issues, November 1997). Those fears seem to have been realized.

Roche, like Merck, has tried to find a twice-daily schedule for its protease inhibitor saquinavir that does not include competing protease inhibitors. The old Invirase formulation of saquinavir has now been largely supplanted by the saquinavir soft gel capsules known as Fortovase. Fortovase contains special lipids that speed saquinavir absorption so that liver enzymes have less chance to break down the drug. But Fortovase capsules are very large, and six are supposed to be taken three times a day.

Roche recently has begun releasing the results of its "TIDBID" trial to test the feasibility of administering Fortovase twice a day. The TIDBID trial is seeking 825 recruits with no prior treatment history or a history limited to nucleoside analogs only. They will receive one of three treatments: Fortovase 1,600 mg twice daily or Fortovase 1,200 mg thrice daily, each in combination with two new nucleoside analogs of choice, or Fortovase at 1,200 mg twice daily plus nelfinavir at 1,250 mg twice daily plus one new nucleoside analog of choice. At the 4th International Congress on Drug Therapy (abstract P68), researchers reported the preliminary results from the 165 study participants with data through 32 weeks. They found that 72% of those taking the twice-daily Fortovase regimen through 32 weeks had viral loads below 400 copies/ml. The equivalent figures were 75% in the thrice-daily Fortovase group and 74% in the dual protease-inhibitor group.

The statistical equivalence of these results unfortunately does not mark any significant improvement in the lot of people with HIV. Twice-daily Fortovase may be more convenient than three times a day, but the total daily pill burden (16 capsules) is only two capsules less than the total thrice-daily burden. Though also given on a twice-a-day schedule, the Fortovase/nelfinavir pill burden, a total of 22 tablets and capsules per day, is largest of all and causes considerably more diarrhea than Fortovase alone. The rationale for combining nelfinavir with Fortovase is that nelfinavir suppresses liver metabolism and raises saquinavir levels, although the magnitude of the effect is less and it may decrease over time (4th International Congress on Drug Therapy, abstract P43). This tactic does not give much advantage over either Fortovase or nelfinavir alone.

Agouron Pharmaceuticals has long considered a twice-daily schedule for its protease inhibitor nelfinavir because of nelfinavir's 3.5- to 5-hour half-life in the body. The company's Study 542 recruited 279 volunteers for a one-year trial of d4T/3TC plus either 750 mg of nelfinavir three times a day (the standard dose) or 1,250 mg of nelfinavir twice a day. After 48 weeks, 80% of those still on either of the study regimens had viral loads below 400 copies/ml while about 70% were below 50 copies/ml (ICAAC, abstract I-216). Peak and trough levels as well as total body exposure were virtually identical on the bid and tid regimens.

The nonnucleoside reverse transcriptase inhibitor delavirdine inhibits liver enzymes similarly to nelfinavir, but this antiviral agent is prescribed on a thrice-daily schedule consisting of four 100 mg tablets each time. Pharmacia & Upjohn, delavirdine's manufacturer, is now studying a twice-daily regimen of nelfinavir (1,250 bid)/delavirdine (600 mg bid) plus d4T and/or ddI at their standard twice-daily doses.

Very preliminary data on this 63-person study, covering only 18 participants on the bid regimens at 12 weeks, were released at the 4th International Congress on Drug Therapy in HIV Infection (abstract P78). Responses are being compared to 19 persons receiving d4T/ddI plus thrice-daily nelfinavir (750 mg) and thrice-daily delavirdine (400 mg or 600 mg). Participants' prior treatment was limited to less than one month of ddI. Given the small numbers of people treated so far to 12 weeks, the results are equivalent statistically for all the regimens, with viral load drops ranging from 2.25 to 3.5 logs (99.4% to 99.9%).

Delavirdine also raises indinavir blood levels such that Pharmacia & Upjohn advises reducing the standard 800 mg tid indinavir dose to 400 or 600 mg. The company is now recruiting for a new trial to test a twice-a-day combination of indinavir (800 mg), delavirdine (600 mg) and AZT (300 mg).


And from Two Times a Day to One

While delavirdine is slowly moving toward a twice-daily schedule, other NNRTIs are achieving once-a-day (qd) status. The FDA, of course, approved efavirenz in September as a once-a-day drug. DuPont's most notable trial of this NNRTI was its DMP-006 protocol, which compared 300 mg bid AZT/150 mg bid 3TC/800 mg tid indinavir to 600 mg qd efavirenz/1,000 mg tid indinavir to 300 mg bid AZT/150 mg bid 3TC/600 mg bid efavirenz. The last of these regimens is very attractive from a simplification point of view. When using Combivir, it consists of one capsule in the morning and four capsules in the evening. (The evening dose will go down to two capsules when the 600 mg efavirenz capsule is introduced next year.) Taking two capsules of indinavir every eight hours was eliminated without any loss in viral suppression over the trial's first 36 weeks (ICAAC, abstract I-103 and 4th International Congress on Drug Therapy, abstract OP5.1).

Trial results may have been distorted by a high dropout rate among those taking indinavir in this trial (41% for AZT/3TC/indinavir, and 30% for efavirenz/indinavir compared to 25% for AZT/3TC/efavirenz). Dropouts, particularly those in the first few weeks before viral suppression is substantial, reduce the apparent success rates in the types of intent-to-treat analyses used in this trial. It is therefore difficult to assess the different treatments' relative efficacy.

It is also notable that cholesterol levels were increased by about the same amount (25%) in those taking both the protease-sparing and the protease-containing triple combinations. Cholesterol levels shot up by 50% in those on the dual efavirenz/indinavir combination.

French doctors at ICAAC described treating 60 antiviral-naive patients with once-daily ddI plus twice-daily d4T and nevirapine (abstract I-97). By week 16, 84% of these patients had viral loads below 500 copies/ml. But nevirapine, the third NNRTI on the market, is also being tried as a once-daily drug.

German doctors reported using a combination of ddI/3TC/nevirapine, all given once a day (4th International Congress on Drug Therapy, abstract OP2.1). They prescribed this regimen to 24 patients who had achieved viral loads below 500 copies/ml on two nucleoside analogs plus a protease inhibitor but were having toxicity problems. Eighteen of the 24 still had viral loads below 500 after 17 to 52 weeks on treatment. Of the six persons whose HIV rebounded, five had had prior treatment with an NNRTI.

Further support for the once-a-day administration of the NNRTI nevirapine came from a Dutch study that followed nevirapine blood levels in six persons receiving either 400 mg qd or 200 mg bid nevirapine (4th International Congress on Drug Therapy, abstract P61). Trough levels between doses were slightly lower with once-daily dosing, but overall, little difference was seen in these blood levels over a 24-hour period.

The nucleoside analog ddI has been investigated in a once-daily schedule since the early stages of its development because of the long intracellular half-life of its active metabolite (greater than 24 hours for ddA triphosphate). Not to be outdone by Glaxo's twice-daily AZT, Bristol-Myers has stepped up tests of once-daily ddI with the expectation that a 400 mg qd schedule will become the FDA-approved standard (see Treatment Issues, November 1997).

Two relevant 50-person studies were presented at the 12th World AIDS Conference, one combining ddI with d4T for 48 weeks (abstract 12351) and the other using ddI with and without hydroxyurea for 16 weeks (abstract 12352). Both found no difference between once-daily and twice-daily ddI.

Investigators at the 4th International Congress on Drug Therapy reported the results of two Bristol-Myers studies (AI454-143 and AI454-146) that combined bid and qd ddI with bid d4T in a total of 176 volunteers with little or no prior treatment (abstracts P80 and P83). Both found no difference between the two ddI schedules, either in terms of CD4 count boost, viral load drop or side effects in the course of 16 to 24 weeks follow-up time. (At week 12, 30% of participants in one trial had viral loads below 500 copies/ml, and 40% in the other had viral loads below 400 regardless of ddI dosing schedule.)

Nucleotide analogs, which are nucleoside analogs activated by adding a phosphate group, generally have very long intercellular half-lives. Adefovir, an adenosine analog under development by Gilead Sciences, has been tested from the beginning on a once-daily schedule. But the 120 mg dose used since phase I turns out to have long-term renal toxicities. Viral load reductions also are modest (in the 0.5 log, or 68%, range, see ICAAC abstract I-108). Studies of a 60 mg once-daily dose are now in progress. The oral prodrug version of PMPA, Gilead's other nucleotide analog based on adenosine, is further behind in development, but it seems more potent and may be a more successful once-a-day drug (12th World AIDS Conference, abstract 12211). PMPA's toxicities remain to be fully defined. Other promising once-daily drugs include the two fluoridated nucleoside analogs FTC (4th International Congress on Drug Therapy, abstract OP7.5) and F-ddA (12th World AIDS Conference, abstracts 22281 and 42263) and Bristol-Myers' new protease inhibitor, BMS-232632 (ICAAC, abstract I-242).

Finally, Bristol-Myers has at last produced samples of its long-promised capsules containing 400 mg of "enteric-coated" ddI beads. Such a formulation would protect the compound from stomach acid, eliminating the need both to package ddI with a noxious buffer and to take the tablets on an empty stomach and separate from other drugs. ddI could then be a true one-pill-a-day medication, easy-to-take agent and achieve its full potential as one of the most potent nucleoside analogs.


Back to GMHC Treatment Issues November 1998 contents page.

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!



  
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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 
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