Published in the Bulletin of Experimental Treatments for AIDS January 1999 issue, by the San Francisco AIDS Foundation.

-- Main Page
-- Top Conference Stories
-- Treatment Guidelines and Immune-Based Therapies
-- Protease Inhibitor Complications And Side Effects
-- HIV Viral Load, Resistance Testing, and Adherence
-- Anti-HIV Drugs And Combinations
-- Opportunistic And Other Conditions
-- Women And Pregnancy, Miscellaneous

January 1999 Table of Contents

Main Page

beta@sfaf.org

Highlights from Recent Conferences -- Anti-HIV Drugs And Combinations

Harvey S. Bartnof, MD

Efavirenz (Sustiva)

Efavirenz May Cause False Positive Marijuana Test

According to the newly updated DHHS antiretroviral treatment, persons taking efavirenz may have a false positive screening test for cannabinoids (marijuana). This means that if a person is taking efavirenz, a drug screening test may falsely register as positive for cannabinoids, even if the person has not inhaled or eaten any marijuana. This has occurred only with the CEDIA DAU multi-level THC assay; it has not occurred with other screening tests or confirmatory tests. Many employers have a policy of surprise urine drug testing, and most people on judicial probation and in drug rehabilitation programs must undergo regular drug testing; not all employers use a confirmatory test after a positive screening test. While the rate of false positive cannabinoid tests has not been determined, people in these situations would be wise to obtain a note from their physician attesting to this possibility. False positive cannabinoid tests have not been reported with the other NNRTIs, nevirapine and delavirdine.

U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. December 1, 1998.

Efavirenz/AZT/3TC Shows Continued Benefit

• Efavirenz triple therapy continues to show benefits at 48 weeks.

• Efavirenz increases blood levels of HDL "good" cholesterol and total cholesterol.

The study that allowed efavirenz triple therapy to be included as a first choice treatment for HIV infection in the updated federal guidelines was itself updated at the 38th ICAAC and 4th ICDTHI meetings (see BETA, October 1998 for earlier results from this study).

The randomized, open-label (not blinded) study included 450 participants (14% women; 40% racial/ethnic minorities). None had previously used protease inhibitors, 3TC, or NNRTIs.

At 48 weeks, using a strict intent-to-treat analysis, those in the efavirenz triple therapy arm (efavirenz/AZT/3TC) showed continued improvement, with 64% having an undetectable HIV RNA viral load (limit of quantitation 50 copies/mL). Benefits were nearly equivalent for those with high baseline viral loads (greater than 100,000 copies/mL) and those with lower baseline viral loads. In comparison, 43% of those in the efavirenz/indinavir arm and 44% of those in the indinavir/AZT/3TC arm had an undetectable viral load. The differences between the efavirenz triple therapy arm and the other two arms were statistically significant. The CD4 counts for all three arms showed continued increases to 170-180 cells/mm³.

Side effects were similar to those seen at 24 weeks (rash, dizziness, insomnia, fatigue, impaired concentration, headache). Withdrawal rates were similar in the two efavirenz arms (25-30%), compared to 41% in the indinavir arm. Withdrawals in the efavirenz arms were mostly due to adverse events including rash, brain-related side effects, gastrointestinal symptoms, or blood cell toxicities. Most of the higher withdrawal rate in the indinavir arm was due to kidney stones (indicated by pain in the back or groin) or nausea.

A previously unreported side effect in the efavirenz arms was a 10-20% increase in total cholesterol and triglyceride levels. Those in the efavirenz/indinavir arm had a greater total cholesterol increase than those in either of the other two arms. Those in the efavirenz/AZT/3TC arm -- which did not include a protease inhibitor -- had the same total cholesterol increase as those in the indinavir/AZT/3TC arm. Increases in total cholesterol reached a plateau after four to eight weeks. Nearly all previous reports of fat increases have been associated with protease inhibitors.

On the positive side, however, levels of HDL "good" cholesterol increased 15% in both the efavirenz arms. This increase was not seen in the indinavir/AZT/3TC arm. HDL levels were still increasing at 24 weeks and had not yet reached a plateau. An increase in HDL levels has not been reported with any other anti-HIV therapies to date. Information on levels of LDL "bad" cholesterol were not presented because participants were not tested in a fasting state.

The authors conclude that the 48-week interim analysis shows that efavirenz/AZT/3TC continues to yield better viral reductions than either efavirenz/indinavir or indinavir/AZT/3TC. CD4 count increases were equivalent in all three arms. While side effect profiles are somewhat different, discontinuation rates due to these effects were more common in the indinavir/AZT/3TC arm. The changes in fat levels are noteworthy. This study is ongoing.

Staszewski, S. and others. A phase III, multicenter, randomized, open-label study to compare the antiretroviral activity and tolerability of efavirenz (EFV) + indinavir (IDV), versus EFV + zidovudine (ZDV) + lamivudine (3TC), versus IDV + ZDV + 3TC at 36 weeks [Study DMP 266-006]. 4th ICDTHI. Abstract OP5.1

Efavirenz Regimens Effective for People with High Viral Load

• Efavirenz-containing regimens are effective even for people with a very high baseline viral load (over 100,000 copies/mL).
• There was a trend towards lower rates of undetectable viral load when baseline viral load was high. 

Manion, D.J. and others. Efficacy of efavirenz-containing regimens in patients with baseline plasma HIV RNA viral loads exceeding 100,000 copies/mL. 36th IDSA. Abstract 447Sa.

Efavirenz Drug Interactions

• Further studies are needed on the combination of efavirenz plus amprenavir; hold off for now.
• When combining efavirenz with indinavir, the indinavir dose should be 1,000 mg every eight hours, with no dose change for efavirenz.
• When combining efavirenz with soft-gel saquinavir (Fortovase), a second protease inhibitor should be added; do not use efavirenz with saquinavir as the only protease inhibitor. Saquinavir levels were reduced 50-62% when given with efavirenz.
• No dose adjustment is necessary when combining efavirenz with any one of the following drugs: nelfinavir, ritonavir, AZT, 3TC, azithromycin (Zithromax), fluconazole (Diflucan), rifampin, famotidine (Pepcid), Mylanta DS.
• Combining efavirenz with clarithromycin (Biaxin) is not recommended; clarithromycin levels were reduced by 26-39%.
• When combining efavirenz and rifabutin, the rifabutin dose should be increased by at least 50%; no dose adjustment is needed for efavirenz.

• When efavirenz is combined with ethinyl estradiol (a contraceptive hormone), no dose adjustment is needed; however, hormone concentration is increased by one-third. 

Fiske, W.D. and others. Summary of pharmacokinetic drug interaction studies with efavirenz. 36th IDSA. Abstract 460.

Abacavir (Ziagen)

Abacavir/AZT/3TC Shows Continued Benefit

• The triple combination of abacavir/AZT/3TC continues to show benefits at 96 weeks
• Study CNA2002 included 60 HIV positive persons who were antiretroviral therapy-naive.
• Abacavir/AZT/3TC can be taken as a simple regimen of two pills twice a day (when the AZT/3TC combination pill Combivir is used). 

Staszewski, S. and others. 96 week experience with a class sparing triple reverse transcriptase nucleoside therapy regimen containing abacavir (1592). 36th IDSA. Abstract 446a Sa.

Abacavir plus Alcohol

• Combining abacavir with alcohol causes a small increase in abacavir concentration, but no changes in alcohol level.
• No dose adjustment is required unless severe liver impairment is present. 

McDowell, .J and others. Evaluation of the pharmacokinetic interaction between abacavir (1592) and ethanol in HIV-infected subjects. 38th ICAAC. Abstract A-67

Abacavir Intensification

• Abacavir intensification shows benefits up to 16 weeks.
• Better viral load reduction is seen if 3TC resistance is present.
• Do not add a single new drug in the case of virologic failure. 

Vernazza, P. and others. Intensification of antiretroviral therapy with abacavir: preliminary 16 week data. 36th IDSA. Abstract 440Sa.

Abacavir Hypersensitivity Reaction Reduction

• Abacavir hypersensitivity reaction abates with steroid and antihistamine therapy.
• Two patients from London were able to continue taking abacavir after treatment.

The hypersensitivity (allergic) reaction to abacavir may be life-threatening if the drug is restarted after being discontinued (see BETA, January 1998). Most patients now taking abacavir are doing so as part of a salvage regimen. Hence, they tend to have few options if abacavir is no longer available as an anti-HIV therapy. Physicians from Chelsea and Westminster Hospital in London have reported on two patients who were able to continue taking abacavir after manifesting the hypersensitivity reaction. This was accomplished by using drugs to block the reaction. The men never stopped taking abacavir, and they have continued to do well.

The first man developed fever, rash, vomiting, weakness, and increased liver enzymes 14 days after starting an abacavir-containing combination regimen. A skin biopsy showed an allergic drug reaction. The man was hospitalized and started on 40 mg daily of prednisolone (a corticosteroid immune blocker), 10 mg twice daily of cetirizine (Zyrtec, an antihistamine), and oral fluids. His symptoms resolved and his liver enzyme levels were improving at the time of the report.

The second man developed fever, rash, and weakness seven days after starting an abacavir-containing combination. After hospitalization, he was treated with 20 mg daily of prednisolone, 10 mg daily of cetirizine, and oral fluids. Two days later, his hypersensitivity symptoms resolved.

Both patients were able to continue taking abacavir while also taking steroid and antihistamine therapy. Note that corticosteroids can themselves be dangerous because they may block the immune system from fighting potentially life-threatening infections. Corticosteroid therapy may also play an unknown role in mitigating the immune benefits of HAART. The drugs also have side effects if taken over prolonged periods. Nonetheless, the therapy did allow continuation of abacavir therapy.

Sullivan, A.K. and others. Abacavir hypersensitivity reaction: continuing therapy with corticosteroid and antihistamine cover. 4th ICDTHI. Abstract P158.

Amprenavir (Agenerase)

Other Protease Inhibitors After Amprenavir

• After an amprenavir-containing combination fails, two other protease combinations are effective.
• Amprenavir-containing regimens show little benefit as salvage therapy.
• Amprenavir may have a unique resistance profile.

Due to cross-resistant HIV strains, high-level failure of one of the first four FDA-approved protease inhibitors usually confers resistance to each of the other protease inhibitors. Amprenavir, an experimental protease inhibitor, has been shown in vitro to have a different resistance profile from the other four drugs in its class. The first evidence of successfully using double protease inhibitor therapy after failure of an amprenavir-containing regimen was reported at the Glasgow conference.

The first report was from AIDS Clinical Trials Group (ACTG) study 373, and included 55 participants whose amprenavir/AZT/3TC or amprenavir monotherapy regimen was failing. The median HIV viral load at the time of drug failure was 24,242 copies/mL. Participants were then given a four-drug, three-class combination of indinavir/nevirapine/d4T/3TC. After eight weeks, over 70% had achieved an undetectable viral load (limit of quantitation 500 copies/mL). After 8-44 weeks, 70-90% had an undetectable viral load. After 24 weeks, the mean CD4 count increase was 89 cells/mm³. Four patients stopped therapy due to virologic rebound, and three patients requested discontinuation. The authors report that the combination was well tolerated. The study is ongoing.

The second report was from Brussels, Belgium. After experiencing a viral load rebound on an amprenavir/AZT/3TC regimen, six patients were switched to ritonavir (400-600 mg twice daily) plus saquinavir (400 mg twice daily) plus d4T plus ddI. After six months, five of the six participants achieved an undetectable viral load (limit of quantitation 500 copies/mL); the median CD4 count increase was 245 cells/mm³. The sixth patient discontinued therapy due to neuropathy (paresthesia) thought to be due to d4T. The five patients are being followed to determine the durability of the response. Further analysis will include resistance testing of the HIV strains present at the time amprenavir was discontinued.

If the results from these two trials are shown to be durable in larger numbers of study participants, amprenavir may be unique among the protease inhibitors currently marketed. This is likely due to the fact that the first resistance mutation that appears is at codon 50, which is different from mutations seen with the other protease inhibitors.

The first evidence on the other side of the amprenavir story is somewhat disappointing. The question of whether an amprenavir-containing salvage regimen would be effective after failure of another protease inhibitor-containing combination was examined by the CNA2007 Study Team. A total of 99 participants had at least 20 weeks of prior protease inhibitor therapy that was failing as determined by a detectable HIV RNA viral load (limit of quantitation 400 copies/mL). At the time of drug failure, the median viral load was five log copies/mL. Participants were then started on a three-class salvage regimen of abacavir/amprenavir/efavirenz. Preliminary results were presented after 16 weeks. Between 7% and 53% achieved an undetectable HIV viral load (limit of quantitation 400 copies/mL). Those with a lower baseline viral load levels (less than 40,000 copies/mL) did better than those with higher baseline viral loads, and participants who had never taken prior NNRTI therapy also did somewhat better. CD4 counts increased by 0-64 cells/mm³. Rash was common, occurring in 38% of those with a viral load less than 40,000 copies/mL and 57% of those with higher viral loads. Another salvage protocol (ACTG 398) will use the above three drugs plus a second protease inhibitor and adefovir dipivoxil.

Murphy, R.L. and others. Treatment with indinavir, nevirapine, stavudine and 3TC following therapy with an amprenavir-containing regimen. 4th ICDTHI. Abstract OP2.4

No Dose Adjustment with Clarithromycin

• No dose adjustment is necessary when amprenavir is combined with clarithromycin.

• The combination results in an 18% non-significant increase in the blood level of amprenavir and no significant changes in the blood level of clarithromycin.

Polk, R.E. and others. Effects of clarithromycin on the pharmacokinetics of amprenavir. 38th ICAAC. Abstract A-73

Indinavir (Crixivan)

Indinavir plus Another Protease Inhibitor Twice Daily

• Benefits were seen with twice-daily dosing of indinavir (400 mg) plus ritonavir (200, 300, or 400 mg).
• The regimen requires no food restrictions, and no fluid requirements for the 400/400 dose.
• No kidney stones were seen in the small number of people studied.

Saah, A. and others. Co-administration of indinavir 1,000 mg and with escalation nelfinavir dose in a twice daily regimen: preliminary safety, pharmacokinetic and anti-viral activity 36th IDSA. Abstract 464.

Nelfinavir (Viracept)

Twice Daily Nelfinavir

• Studies of twice-daily nelfinavir dosing show continued benefits up to one year.

Post, J. and others. An open label trial changing nelfinavir dosing from tid to bid with pharmacokinetic analysis, a preliminary report. 36th IDSA. Abstract 465.

Saquinavir (Fortovase, Invirase)

Twice Daily Saquinavir Shows Benefit

• Twice daily soft-gel saquinavir (Fortovase) in combination regimens shows benefits up to 24 weeks.

Farthing, C. and others. Fortovase (SQV) soft gel capsule BID regimens in combination with 2 nucleosides or nelfinavir plus 1 nucleoside in HIV-1 infected patients. 38th ICAAC. Abstract I-105.

Twice Daily Saquinavir plus Ritonavir

• Twice daily dosing of saquinavir may be possible with a small dose of ritonavir (e.g., a twice daily regimen of hard-gel saquinavir [Invirase] 600-800 mg, plus ritonavir 100 mg-200 mg, plus d4T plus 3TC).
• Improvements in abnormal body fat redistribution occurred after switching from a standard indinavir-containing triple regimen.

Although the most commonly used double protease inhibitor combination is 400 mg each twice daily of ritonavir and saquinavir, Jacques Leibowitch, MD, and colleagues from France have reported benefits using different twice-daily doses of each drug. When a "baby" dose of 100 mg of ritonavir was prescribed, 800 mg of hard-gel saquinavir was used. When 200 mg of ritonavir was prescribed, 600 mg of hard-gel saquinavir was used.

Before switching to the above regimen, the 52 people studied had been taking a standard indinavir/AZT/3TC triple combination regimen for a median of nine months. At the time of the switch, these persons' therapy was not failing. The interim results after a median of eight months on the new quadruple regimen showed that undetectable HIV viral load levels were maintained. Also, immune measurements were maintained or improved. Adherence also improved. "Dysmorphic lipodystrophy" (body fat redistribution) reportedly decreased after switching from the indinavir regimen to the ritonair/saquinavir regimen; specific laboratory test results and rates of lipodystrophy were not stated in the abstract. Given that the standard 400 mg each twice-daily dose of saquinavir and ritonavir have been associated in initial reports with high rates of fat redistribution and lipid abnormalities, this new dosing schedule is worth watching.

Liebowitch, J. and other. Alleviating antiviral constraints for the sake of long term efficacy, tolerance and compliance: hard gel capsule saquinavir + "baby" dose ritonavir-containing regimens, a series of modern HAART solution? 4th ICDTHI. Abstract P179.

Ritonavir (Norvir)

Ritonavir Intolerance Better Understood

• Ritonavir intolerance is significantly associated with low body fat, micronutrient deficiencies, lack of micronutrient supplements, and therapy with anabolic steroids.
• Intolerance is associated with higher blood levels of ritonavir

While ritonavir is extremely potent, its tolerability is limited, mainly due to gastrointestinal side effects. Many people with HIV who are taking the drug are doing so at a lower dose in combination with saquinavir. Researchers from Brown University have determined factors that are associated with ritonavir intolerance.

The analysis included a retrospective chart review of 322 people with HIV. A total of 74 were taking or had taken ritonavir. At the time of the analysis, 57% were still taking the drug, while 43% had discontinued, almost always due to gastrointestinal symptoms. Among the 42 who were still taking ritonavir, 77% were taking a full dose (600 mg twice daily). The other 23% were on a reduced dosage of 400 mg twice daily in combination with saquinavir at the same dosage.

At baseline, the study revealed a significantly higher rate of low body fat (measured by bioelectric impedance analysis) among ritonavir-intolerant persons (26%) compared to ritonavir-tolerant persons (6%). Also, low levels of micronutrients (vitamins and minerals) were significantly more common in ritonavir-intolerant persons (58%) compared to ritonavir-tolerant persons (27%). Significantly fewer ritonavir-intolerant persons were taking micronutrient supplements (32%) than ritonavir-tolerant persons (69%). Lastly, a significantly greater percentage of ritonavir-intolerant persons were taking anabolic steroid therapy (66%) than ritonavir-tolerant persons (39%).

The results of this study suggest a patient profile that is more likely to be tolerant of ritonavir therapy. That profile would include normal body fat levels, normal blood micronutrient levels, and supplemental therapy with micronutrients, but not use of anabolic agents. The authors hypothesize that anabolic agents may partly contribute to the low body fat levels that are associated with ritonavir intolerance.

In a second study, researchers from the University of Genoa found that in ritonavir-intolerant persons, drug levels in the blood were significantly higher than drug blood levels in those who tolerated the drug. Fifteen persons were included in this study. The authors concluded that "individualization of dosage regimen based on plasma concentrations may result in a substantial increase in the percentage of patients tolerating ritonavir."

Melbourne, K. and others. Tolerability and body composition of HIV-infected individuals on ritonavir-containing regimens. 38th ICAAC. Abstract I-89.

Ritonavir Benefits HIV Negative Boy

In the first published report of ritonavir usage in an HIV negative person, A. Broderick, MD, from Our Lady’s Hospital in Dublin, Ireland, was able to control a 14-year-old boy’s refractory epilepsy using the drug. Despite a high dosage, the boy's physicians were unable to obtain a high enough blood level of phenytoin (Dilantin), a common anti-convulsant drug. This caused the boy to have 30 seizures in one day. Knowing that phenytoin is metabolized by the same liver enzyme that is inhibited by ritonavir, the physicians added ritonavir to the boy's regimen. Fortunately, this caused phenytoin levels to rise into a high therapeutic range, and the seizures stopped. Eventually, the physicians decided to replace ritonavir with cimetidine (Tagamet), an antihistamine that also inhibits the CP450 liver enzyme system but which has a slower onset of action. After 54 days of hospitalization, the boy was able to go home with his seizures under control. This is the first report of the use of ritonavir for a non-HIV-related reason.

Broderick, A. and others. A novel use of ritonavir. 4th ICDTHI. Abstract P45.

Technique Makes Liquid Ritonavir Easier to Swallow

Problems with the manufacturing of the capsule formulation of ritonavir has led to a shortage of capsules (see BETA, October 1998). In the interim, the liquid formulation of ritonavir is available as a substitute. Unfortunately, the taste of liquid ritonavir ranks among the least palatable substances known, in spite of its alcohol content. For those who do not like having to coat their mouth with peanut butter before taking liquid ritonavir or following it with a chocolate syrup chaser, Kathryn Kocurek, MD, has another suggestion.

In her presentation at a recent International AIDS Society-USA (IAS-USA) conference, Kocurek described the use of empty gel capsules. Liquid ritonavir can be squirted inside one-half of the capsule with a syringe. Then the two halves of the capsule are put together, creating a homemade ritonavir capsule that can be swallowed. The gel capsule dissolves in the stomach. Empty gel capsules can be purchased at many health food stores and vitamin stores.

Kocurek, K. Case vignettes; issues in antiretroviral management: initial therapy. Current Challenges in HIV Disease Conference. International AIDS Society-USA. October 28, 1998.

Delavirdine (Rescriptor)

Can Delavirdine be Taken Twice Daily?

• 600 mg twice-daily delavirdine was compared to the standard 400 mg three-times-daily regimen.
• Drug exposures were nearly equivalent.
• A twice-daily, three-class, four-drug combination (delavirdine/nelfinavir/d4T/ddI) is equivalent to a similar regimen with three-times-daily delavirdine and nelfinavir.

Wathen, L.K. and others. Antiviral efficacy of twice daily Rescriptor plus nelfinavir, didanosine (ddI) and stavudine (d4T) in an open-label randomized study of triple and quadruple treatment regimens in HIV-1 infected individuals. 4th ICDTHI. Abstract P78.

Delavirdine in a Protease-Sparing Regimen

• The protease-sparing combination delavirdine/AZT/3TC shows benefits at one year.
• 60% maintained undetectable viral load (limit of quantitation 40 copies/mL).
• CD4 count increase was 90 cells/mm³.

Wathen, L.K. and others. Inverse relationship between viral burden nadir and length of antiviral efficacy in HIV-1 infected patients treated with Rescriptor (delavirdine) + Retrovir (AZT) + Epivir (3TC). 4th ICDTHI. Abstract P79.

Nevirapine (Viramune)

Nevirapine Rash Reduced with Prednisone

• Nevirapine-induced rash was reduced to less than 1% if prednisone (40-50 mg daily) was used.

A major side effect of nevirapine is a skin rash that may be life-threatening. A rash occurs in approximately 20% of those who take the drug. A significant nevirapine-induced rash is the most common reason for stopping the drug. A gradual dose increase during the first two weeks helps to decrease the occurrence of rashes.

R. Kaspar, MD, from the David Powell Clinic in Austin, Texas, reported that a short course of prednisone, an immune blocker, markedly decreases the nevirapine rash rate. In an uncontrolled case series study, Kaspar prescribed 40-50 mg of prednisone daily during the two-week induction period. Among 83 persons who took the drug when they started a nevirapine-containing HAART regimen, only one developed a significant rash. That rash was very mild and did not requiring discontinuation of nevirapine. This compared with a rash rate of 14% (10 of 72) among persons who started a nevirapine-containing HAART regimen without prednisone.

Prednisone is a potent steroid immune blocker that usually cannot be given to patients who have hypertension (high blood pressure), diabetes, or active opportunistic infections. Some physicians may consider prednisone therapy in this circumstance to be very aggressive or even risky, due to its immune suppressive characteristics. Many physicians prescribe preventive antihistamines to help decrease the rash rate from nevirapine.

Limitations of this study include its uncontrolled nature, and the potential confounding influences of different CD4 counts and HIV viral load levels between the two groups. Side effects of prednisone include fluid retention, weight gain, high blood pressure, diabetes, stomach ulcers, and elevated mood.

Kaspar, R. Prednisone therapy during the induction phase of nevirapine therapy appears to reduce the incidence of nevirapine-associated rash. 38th ICAAC. Abstract I-64a.

Nevirapine Induces Opiate Withdrawal

• Nevirapine was found to induce opiate withdrawal in seven persons receiving methadone.
• Methadone doses may need to be increased or nevirapine may need to be avoided in HIV positive patients taking methadone.

Researchers from Yale University in New Haven, Connecticut, described seven HIV positive persons on methadone maintenance therapy who experienced opiate withdrawal symptoms four to eight days after starting nevirapine. Methadone blood levels were determined to be therapeutic for two of three patients in whom it was measured before nevirapine was started. The mean dose of methadone before starting nevirapine was 76 mg daily, with a range of 30-115 mg. At the time withdrawal symptoms occurred, the blood level of methadone in the three patients in whom it was measured was extremely low (less than 0.2 micrograms/mL).

In three of the patients who were able to continue nevirapine treatment, their daily methadone dose was increased to at least 150 mg daily. In three other patients, the methadone dose was increased unsuccessfully. Among the seven patients, four discontinued nevirapine and one declined further antiretroviral therapy.

Nevirapine is a potent inducer of the liver CYP3A4 isoenzyme, which likely causes faster metabolism of methadone. The authors state that their findings underscore the need for drug interaction studies with anti-HIV drugs and methadone. Given its easy once or twice daily dosing, nevirapine is popular among drug-using populations.

Altice, F.L. and other. Nevirapine induced methadone withdrawal: implications for antiretroviral treatment of opiate dependent HIV infected patients. 36th IDSA. Abstract 463.

Can Nevirapine be Given Once Daily?

• A nevirapine dose of 400 mg once daily may be equivalent to 200 mg twice daily.

Van Heeswijk, R.P.G. and others. The plasma pharmacokinetics of nevirapine (Viramune®) in a once daily and twice daily regimen. 4th ICDTHI. Abstract P61.

Older Nucleoside Analogs

ddI Once Daily

• Several studies show benefits of ddI (Videx) taken once daily.

Gill, J. and others. Didanosine administered once daily, interim results of a randomized double blind study. 4th ICDTHI. Abstract P82.

ddC in Twice Daily Regimen

• ddC (Hivid) was tried in a twice daily regimen (1.125 mg twice daily).
• Use of the lower dose is an attempt to increase adherence compared to the standard three-times-daily ddC regimen.

Moyle, G.J. and others. Use of zalcitabine in twice daily regimens. 38th ICAAC. Abstract I-208.

Double Nucleoside Analog Therapy

• Double nucleoside analog therapy (i.e., without a protease inhibitor or NNRTI) may be sufficient for a small minority of people with very early disease.
• After one to three years of follow-up, 10% of clinic patients maintained an undetectable HIV viral load.

Researchers from the University of Alabama at Birmingham examined HIV positive persons at their clinic who continue to do well on only double nucleoside analog therapy. The authors acknowledge that many HIV clinics and practices have such patients, despite the current standard of care of triple drug therapy that usually includes a protease inhibitor or NNRTI.

The authors found 236 current clinic patients who had been receiving dual nucleoside analog therapy for more than six months. Among those, 23 (10%) maintained an undetectable HIV viral load (limit of quantitation 25 copies/mL) for at least 12 months. The median follow-up was 21 months, with a range of 12-37 months. The median CD4 count increase was 145 cells/mm³, from a median baseline of 511 cells/mm³. The median baseline HIV viral load was 2,843 copies/mL. Over half had received nucleoside analog monotherapy prior to starting double therapy. The three combinations used were AZT/3TC (48%), d4T/3TC (26%), and d4T/ddI (22%). Twelve of the 23 had an isolated detectable viral load at some point, with 42% of them experiencing non-adherence or toxicity.

The authors conclude that a small percentage of HIV positive people can maintain extremely low viral loads for up to three years with only double nucleoside analog therapy. Most of them have early disease and limited treatment experience. However, when and if these persons experience virologic breakthrough with increasing viral loads and drug resistance, their future treatment options will be more limited.

Next section of highlights from recent conferences:
Opportunistic and Other Conditions

Page last updated 15 January 1999

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