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Being Alive

Treatment of HIV Infection with Indinavir and Nevirapine: An Observational Study of 45 Patients


Being Alive 1997 May 5: 6

Eighty patients with hiv infection began treatment over several months in a private practice setting with indinavir and nevirapine started simultaneously. As of this writing, 45 have had at least one set of follow-up laboratory results and are therefore included in these data. The drugs were started in combination with the hope that the simultaneous use of two new antiretroviral agents which are able to markedly suppress viral replication, and to which hiv is unable to develop cross-resistance, might lead to a sustained suppression of replication. Ritonavir and saquinavir used in combination offer this possibility as well. Indinavir was chosen to avoid the toxicity and drug interaction problems associated with ritonavir and because its absorption is more reliable than that of saquinavir.

Methods All patients who had baseline laboratory tests within one month before starting the drugs, and who have had at least one follow-up set of labs, have been included in this report. The ages ranged between 22 and 66. Four were women and 41 were men. All 45 had been taking and continued to take low dose naltrexone 3 mg at bedtime as an immune enhancing agent. They had been on it a mean of 32 months. Thirty of the patients were taking AZT and 3TC when they started the two additional antivirals. This group of 30 had been on AZT and 3TC for a mean of 11 months. None were on it for less than 4 months. Two patients were on 3TC without AZT before starting indinavir and nevirapine. At the beginning of the observational period, the mean CD4s were 235 with a CD4 range from 5 to 549. The mean baseline hiv RNA PCR was 74,210.

Baseline labs including hiv RNA PCR, lymphocyte subsets, CBC and differential, chemscreen and urinalysis were done within 30 days before starting the new antiretrovirals. The same labs were repeated every 4 to 8 weeks. The changes in laboratory results were calculated by comparing the most recent set of tests with the baseline. The mean time from the first day of medication administration to the most recent labs in the 45 patients was 121 days or 4 months. Patients were prescribed indinavir at 800 mgs every eight hours and nevirapine 200 mg a day for 14 days, then 200 mg twice a day.

Forty-two of the 45 patients showed a drop in viral load to less than 400 or not detected on the first follow-up hiv RNA PCR test. One patient had a rise from less than 400 to 3000 on the second follow-up test when he stopped following the food restrictions recommended with indinavir. He resumed the regimen after seeing the viral load rise. His viral load returned to less than 400 on the two tests thereafter. The other 41 remained at less than 400, some now for as long as 70 months. The CD4 absolute number rose from means of 235 to 349, a rise of 114 or 49%. The CD4 percentage rose from means of 15.2% to 20.4%. The only other significant laboratory change was a rise in serum cholesterol from means of 159 to 209, a dramatic change for a group of people with hiv infection.

Clinical Results Patients reported significant improvements in energy, appetite, mood and outlook. Mean weight gain was 8 pounds. Several more introspective patients noticed an improvement in mental clarity. A number of patients said they had not felt this well in years. No opportunistic infections occurred in the course of the study. Twelve patients with chronic symptomatic sinusitis unresponsive to standard therapies reported complete or near complete clearing of symptoms. Recurrent folliculitis cleared in several patients although nevirapine related rashes and indinavir related dry skin was a problem for some. None of the 45 patients stopped either drug. The usual indinavir side effects occurred and cleared in 14 to 21 days in about three-quarters of the patients.

Indinavir Blood Levels The 3 patients who did not show dramatic drops in viral load all described no indinavir side effects and two still have none on 1600 mg every eight hours. Most of the patients in the study have had their indinavir doses increased to 1000 mg or 1200 mg every eight hours in the last few weeks. This has been in response to the Boehringer Ingelheim study that added nevirapine in 19 patients taking indinavir. The study showed a 27% drop in mean indinavir blood levels, leading to the recommendation that clinicians combining the two drugs consider raising the indinavir dose to 1000 mg every eight hours. However, of greater concern is the fact that before nevirapine was added the study showed a threefold or 300% variation in indinavir blood levels among the 19 patients.

This is not surprising in view of our decades of experience in adjusting doses of drugs used to treat such diseases as epilepsy, congestive heart failure, bipolar disorder and cardiac arrhythmias using standard laboratory tests for blood levels. The general experience is that dosages of these drugs must be adjusted over at least a 300% range to achieve the standard therapeutic blood levels. Presumably, rates of both absorption and excretion play roles in these blood level variations which probably occur with most drugs. The protease inhibitors are clearly drugs for which achievement of adequate antiviral blood levels is crucial in order to avoid or postpone development of drug resistance.

However, the recommended doses are standardized. No testing of drug blood levels is recommended by the FDA or pharmaceutical companies for protease inhibitors and none are commercially available. I presume that the failure to achieve therapeutic blood levels accounts for most of the 20% or so of patients who appear to fail to respond dramatically to the new antivirals. I am presently increasing indinavir dosage in those patients who got little side effects when the drug was initially prescribed even if they had a satisfactory response in viral load and CD4s. I am arranging for the availability of indinavir and nevirapine blood level testing and expect to incorporate these as routine clinical tools in my practice.

The AZT/3TC Sub-group I conducted a private practice study of 20 patients on AZT, 3TC and naltrexone before the protease inhibitors became available. It showed a rise in CD4s from means of 88 to 194 which represents a rise of 120% over a 6 month period. This compared with the Glaxo Wellcome study where the CD4s rose from 352 to 392 which represents an 11% increase. The Glaxo study was the basis for the licensing of 3TC. All of these earlier patients and an additional 10 on AZT and 3TC are included in the 45 patients in this study. Thus, I have a number of patients who have experienced a sustained rise in CD4s averaging about 100 and a year later an additional CD4 rise averaging more than 100 when indinavir and nevirapine were added to their regimen.

The original AZT/3TC group appeared to have a greater rise in CD4s than in the Glaxo study when these two drugs were started because they were also on naltrexone. Although naltrexone is playing a role in the CD4 rise with indinavir and nevirapine, there is no reported indinavir/nevirapine group with whom I can compare results.

The Cholesterol Rise Cholesterol blood levels are chronically low in hiv infected patients. This is because of impairment of intestinal absorption of fats caused by defective bile production and by chronic hiv infection of the cells lining the small intestine. The increase in cholesterol raises the possibility that a large percentage of the hiv infected cells lining the small intestine have died in the course of their usual 3 to 6 month life cycle and have been replaced by uninfected cells. If true, this would parallel the results of the recent Amsterdam study in which biopsies of the tonsils in 10 patients who have been on indinavir, AZT, and 3TC for 6 months showed the disappearance of hiv from this lymphatic tissue. Both of these findings support the merit of carefully chosen combinations of new generation antiretrovirals.

Bernard Bihari, M.D., is in private practice in New York City. He can be reached at 212.929.4196.


Information in this article was accurate in May 5, 1997. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.