Two studies on the use of ritonavir for HIV infection

1. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease.

Eligibility

• CD4+ count > 50; plasma concentration of HIV p24 >10 pg/ml; age > 18.

Protocol

• patients receiving anti-retrovirals: 2 week washout period.
• 4 week randomization phase:
  Group 1: 300 mg ritonavir bid (600 mg daily), 400 mg bid (800 mg) or placebo.
  Group 2: 500 mg bid (1000 mg), 600 mg bid (1200 mg) or placebo.
• maintenance phase (up to 32 weeks reported here):
  patients taking drug continued same dose, those on placebo randomized to one of the two drug doses in their group.

• CD4+ lymphocyte counts (expressed as median values in the results).
• HIV-1 p24 antigenemia (expressed as median values in the results).
• viral RNA by bDNA assay, lower limit of detection: 10,000 RNA equivalents/ml (expressed as mean value in results). In a subset of 17 patients, viral RNA measured by a more sensitive PCR method.
• ritonavir levels.

84 patients enrolled (3 women), 39 in group 1, 45 in group 2.
Baseline CD4+, p24, viral RNA and prior use of antiretrovirals (60-85%) were not statistically different (except for CD4+ in placebo (lowest) vs. 1000 mg group).

• CD4+ counts

  At 4 weeks (end of the placebo controlled phase), there was a significant increase in CD4+ counts at all dose ranges (median increase around 100 cells/mm3).

  Thereafter, the counts remained increased until week 12, then began to drop back towards baseline by week 32 in all groups except for the highest dose group (1200 mg total daily dose), where the median increase remained significant at 230 cells/mm3.

• HIV p24 and viral RNA levels

  At 4 weeks, median p24 levels were significantly decreased (by almost 100%) at all 4 dose levels. Similarly, viral RNA was significantly reduced, by about 1 log copy/ml, at all 4 doses.

  Thereafter, viral RNA returned towards baseline by week 16 in the two lower dose groups. In the higher dose groups, there was a more gradual return towards baseline. The 1000 mg/day group reached baseline around week 32, the 1200 mg group remained significantly lower than baseline at week 32 (by 0.81 log, in 7 patients). No statistics are given for p24 antigenemia during the maintenance phase.

• Pharmacokinetics and adverse effects

  Plasma measurements confirmed good oral bioavailability. Side effects were very common, seen in 100% of patients at the highest dose. Main drug related adverse effects were nausea, circumoral paresthesias, elevations in cholesterol, triglycerides and transaminases. During the initial 4-week phase, from the 84 enrolled there were 8 withdrawals, 4 due to the drug (1 nausea, 3 transaminases). During the maintenance phase, out of 76 patients there were 25 discontinuations, 6 due to the drug (3 nausea, 3 transaminases).

2. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection.

Eligibility

• CD4+ count 50-500; viral load: HIV RNA>25,000 copies/ml; no substantial hepatic abnormalities.

Protocol

• 2 week washout period
• 4 week randomization phase:
  Group 1: 200 mg ritonavir tid (600 mg daily), 300 mg tid (900 mg) or placebo.
  Group 2: 200 mg qid (800 mg), 300 mg qid (1200 mg) or placebo.
• 8 week extension phase:
  patients taking drug continued same dose, those on placebo randomized to one of the two drug doses in their group.

• CD4+ lymphocyte counts (expressed as median values in the results).
• viral RNA by bDNA assay, lower limit of detection: 10,000 RNA equivalents/ml (expressed as mean value in results). In a subset of 20 patients, viral RNA measured by a more sensitive PCR method.
• ritonavir levels.

62 patients enrolled (2 women), 31 in group 1, 31 in group 2.
Baseline CD4+, viral RNA and prior use of antiretrovirals were not statistically different between groups.

• CD4+ counts

  At 4 weeks and 12 weeks there were significant increases in CD4+ counts at all dose levels, although these increases did not correlate well with the actual doses received.

• Viral RNA levels

  Viral RNA levels decreased, maximally at two weeks, then began to rise again towards baseline. At 12 weeks, there was still a significant decrease in viral RNA of 0.50 log in all dose groups. Viral RNA levels measured by the more sensitive PCR method in 20 patients indicated that the actual reduction in viral RNA was probably underestimated by the bDNA assay.

• Pharmacokinetics and adverse effects

  Plasma measurements confirmed good oral bioavailability. Side effects were very common. Most common were diarrhea, nausea, headache and weakness. Circumoral paresthesias, elevations in cholesterol, triglycerides and liver enzymes were also seen. Of note, transaminase elevations occurred with the same frequency in placebo and drug groups, but GGTP elevation occurred only in the drug groups. There were 10 withdrawals overall, 3 felt to be due to the drug.

Summary comparison of the methods of the two trials

                   European Study             U.S. Study

Eligibility        CD4+ > 50                  CD4+ 50-500
                   HIV p24 > 10 pg/ml         Viral load > 25 000

Pre-               2 week washout             2 week washout
randomization      from anti-retrovirals      from antiretrovirals

4-week study       Group 1: 600 mg,           Group 1: 600 mg,
                   800 mg or placebo          900 mg or placebo

                   Group 2: 1000 mg,          Group 2: 800 mg,
                   1200 mg or placebo         1200 mg or placebo

Continuation       32 weeks                   12 weeks 

Comment

In neither study do the authors state how they calculated a mean viral RNA titer when a patient's titers were below the limit of detection of the bDNA assay (10,000). Did they use 10000, 5000, zero or some other number to calculate the mean, and could a difference between the approach used in the two studies account for the apparent earlier loss of effectiveness in the US study?

Both of these studies demonstrate impressive anti-viral activity of ritonavir, a protease inhibitor, which decreases after several weeks of treatment, however, due to the emergence of resistant mutations. As the authors of both studies state, the place of ritonavir in the anti-viral armamentarium, particularly in combination therapy with the nucleoside analogues (such as AZT, ddI, ddC), remains to be determined. Its antiviral activity appears to be greater than that of the other drugs, at least initially, its pharmacokinetics are favorable, and it is fairly well tolerated. Clearly, there will be more trials with this drug, particularly in combination with other therapy.

12/10/95

Reader comments

Protease inhibitors cause a transient drop in viral levels. Levels increase in time because of appearance of drug resistant strains.

Since there is no evidence of clinical improvement in the patients, it is very unwise to promote mutant organisms that once transmitted result in a more difficult situation to treat.

The FDA has become nothing but the ever compliant wagging tail of nonphysician AIDS activists. This is a dangerous problem that must be stopped.

Mark I. Klein, MD

Drug resistant mutations of various micro-organisms are becoming a major problem in infectious diseases. Multi-drug resistant tuberculosis, vancomycin resistant enterococci, penicillin resistant pneumococci ...

The basic cause is always some variant of the conflict between private and public interests: using the most potent and broad spectrum antibiotics for the individual patient, feeding livestock antibiotics for higher yields vs. the need to preserve the effectiveness of these drugs.

If I were involved in hospital epidemiology, I would probably look at things differently than if I were a patient with r/o staph sepsis in the same hospital.

With the use of anti-viral therapy in HIV, the problem is very complicated. The disease is deadly, strikes a young population and is prevalent in groups that have traditionally had reasons to fear the "authorities". This is not fertile ground for quiet, rational debate. Furthermore, we live in an era when the non-physician public at large is increasingly taking health matters into its own hands and is less inclined to trust the medical profession. For all these reasons, I don't think the FDA can make any decisions without a lot of problems. I'm willing to allow it to err on the side of "liberalism".

I do think we need to pay attention to the potential danger of drug-resistant HIV mutations, just as we do to drug-resistant TB. We need to study to what extent these are transmissible from one person to another and to concentrate on combination therapy. -- mj

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