HIV Drug Resistance in the US Exceeds Previous Estimates
More than three-quarters of HIV patients with a measurable viral load who are receiving care in the US carry strains of the virus that are resistant to drug therapy. This high prevalence of detectable drug-resistant virus during the first three years of the HAART (highly active antiretroviral therapy) era (early 1996-early 1999) has significant implications for efficacy of treatment interventions and for the transmission of HIV drug resistance.

Blood plasma samples taken in 1999 from 1,647 men and women enrolled in the HIV Cost and Service Utilization Study (HCSUS), a longitudinal study representative of all HIV-infected adults throughout the US who received medical care in early 1996, were evaluated for HIV drug susceptibility. Resistance assays were performed on banked frozen (-70º C) specimens of plasma collected from each subject at enrollment. The HIV drug susceptibility was determined by testing plasma samples, using the PhenoSense HIV-1 assay (Virologic) a new phenotypic assay. This approach has been shown to significantly enhance viral resistance testing. Of the 1,647 samples, 1,167 (71%) had more than 500 HIV RNA copies/mL; 1,080 (93%) of these were successfully phenotyped. Results were weighted to represent the 132,442 (63%) of the 209,000 US adult HIV patients under care in early 1996 who survived until 1999 who had more than 500 HIV RNA copies/mL.

The estimated prevalence of persons with drug-resistant virus in this population was 78%. Prevalence of drug resistance varied by drug class: 70% for nucleoside reverse transcriptase inhibitor (NRTI), 31% for non-nucleoside reverse transcriptase inhibitor (NNRTI), and 42% for protease inhibitor (PI). Drug resistance was particularly high (87%) among persons who were receiving antiretroviral therapy at the time of testing, often consisting of potent "cocktails" of three or more drugs. This compared with 41% among those who had received antiretroviral therapy but stopped before testing.

The likelihood of resistance was significantly associated with more advanced HIV disease (84% in CDC stage C) and lowest CD4 cell count (90% with CD4 count of less than 50 at lowest level) but not current CD4 cell count. Prevalence of drug resistance also was significantly associated with greater access to healthcare and treatment (as in non-Hispanic white mates, highly educated, privately insured, and men having sex with men as a risk factor). In addition, while drug resistance is more common in those receiving treatment, drug-resistant strains of HIV can be transmitted through sexual contact, with up to 20% of newly diagnosed HIV patients having drug resistant HIV strains before the patients themselves even start antiretroviral therapy.

These findings stress the need for drug resistance testing since this can identify which drugs will not be effective for a patient. While insurance coverage varies, resistance testing is cost beneficial, since not using a ineffective drug saves money. Also, it is obvious that medical practitioners must use antiretrovirals as intelligently as possible because each drug has pharmacologic interactions with other drugs, its own adverse reactions, and its own resistance development (Richman, D.D., et al. 41st ICAAC Abstracts 2001: Addendum. December 16-19, 2001, p14).

Abacavir + Lamivudine + Zidovudine (Trizivir™, GlaxoSmithKline)
Switching to Trizivir, a combination of lamivudine 150 mg, abacavir 300 mg, and zidovudine 300 mg in one tablet administered twice daily, offers a potent, simplified, and convenient regimen with equivalent efficacy to continued highly active antiretroviral therapy (HAART) in HIV-infected patients.

In an open-label comparison study of current triple HAART versus a switch to Trizivir, 209 patients were randomized to receive either Trizivir (106 pts) or to continue HAART (103 pts). Patients with plasma HIV-1 RNA of less than 400 copies/mL for the previous six months and less than 50 copies/mL at screening were enrolled. Efficacy, safety, tolerability, adherence, and patient satisfaction were assessed after 48 weeks. The primary end point was treatment failure defined as virologic failure (two consecutive HIV-1 RNA values over 400 copies/mL) or premature discontinuation of randomized treatment by 48 weeks. Treatment adherence was measured by a patient self-report questionnaire.

At week 48, proportions of treatment failures were equivalent in the Trizivir (22%; 23/106) and continued HAART (22%; 23/103) arms of the study. Virologic failure occurred in the first 24 weeks in five patients on Trizivir and one patient on continued HAART but three of the five in the Trizivir arm reached HIV/RNA of less than 400 copies/mL by week 48. Premature discontinuation took place in 18 Trizivir-treated patients, 11 due to suspected hypersensitivity reaction, versus 22 patients on continued HAART. Furthermore, significant decreases in fasting total cholesterol and triglycerides were noted in the Trizivir arm of the study. Also, patients on Trizivir found their treatment easier to take (Katlama, C., et al. 41st ICAAC Abstracts 2001, p324).

Tenofovir DF (Viread™, Gilead Sciences)
At nearly two years of treatment, tenofovir DF, a single-tablet, once-daily NRTI with potent activity against wild-type and nucleoside-resistant HIV, is well tolerated and provides continued antiviral activity in treatment-experienced, HIV-infected patients with high levels of nucleoside resistance.

A 48-week study was designed to assess the safety and efficacy of open-label tenofovir DF 300 mg, administering in combination with other antiretroviral agents to treatment-experienced, HIV-infected patients. The study was set up in two phases: a blinded phase lasting 48 weeks and an open-label extension phase for 135 patients who completed the blinded phase and elected to receive tenofovir 300 mg once-daily in addition to their background antiretroviral therapy.

In the blinded phase, a total of 189 highly treatment-experienced patients were randomized to receive tenofovir DF 75 mg, 150 mg, or 300 mg once daily as a single tablet or placebo, in addition to their stable antiretroviral therapy. Through 48 weeks of treatment, tenofovir 300 mg once daily provided continued antiviral suppression,-0.62 log10 copies/mL reduction in HIV RNA from baseline, with no evidence of treatment-related toxicity.

At week 72, in patients in the tenofovir DF 300 mg open-label group, the mean change in HIV RNA from baseline was -63 log10 copies/mL, while, at week 96, the mean change in HIV RNA from baseline was -0.87 log10 copies/mL. In an assessment of the emergence of nucleoside-associated HIV retroviral therapy (RT) mutations, through 96 weeks of treatment there was infrequent (3%) development of RT mutations associated with tenofovir DF therapy and continued HIV RNA suppression. The clinical adverse events rate, laboratory abnormalities and discontinuation rate was comparable in both phases of the study (Schooley, R., et al. 41st ICAAC Abstracts 2001, p348).

Proactive Switching
Nelfinavir (Viracept®; Agouron) + 2 NRTIs
Efavirenz (Sustiva®; DuPont) + 2 NRTIs
Proactive switching of antiretroviral triple combination regimens seems to have a better virologic outcome than the current standard treatment strategies in antiretroviral-naïve, HIV-infected patients, reported Dr. E. Negredo, infectious diseases specialist with Lluita contra la SIDA Foundation, Badalona, Spain, speaking for the SWATCH Study team.

In a multicenter, international, prospective trial, 161 HIV-infected patients who were treatment naïve were randomized to one of three study arms: A, containing stavudine (d4T)/didanosine (ddI)/efavirenz; B, containing zidovudine (ZDV), lamivudine (3TC)/nelfinavir; or C, switching between regimens A and B every three months. Viral load, CD4 cell counts, and routine blood tests were determined at baseline and every 12 weeks, as well as were clinical events and adherence.

At the 48th-week follow-up, 116 patients were available for evaluation. A total of 70% of the patients who were switching between regimens A and B every three months had a viral load of less than 400 copies/mL versus 60.5% of patients in the other two groups. Virologic failure was reported in eight patients in arm A, seven patients in arm B, and no patients in arm C, the proactive switching regimen. No significant differences were seen in the median CD4 cell increases.

Total cholesterol rose a mean 32, 26, and 19 mg/dL in arms A, B, and C, respectively, showing a trend in favor of proactive switching. Six patients presented with lipodystrophy; three in arm A and three in arm B. A significant fat loss was observed in limbs in all three treatment groups, with no differences between them. Adherence to treatment was comparable in all study arms (Negredo, E., et al. 41st ICAAC Abstracts 2001, p324).

Atazanavir (BMS-232632; Bristol-Myers Squibb)
Atazanavir, an investigational protease inhibitor, has been shown to be safe, effective, and well tolerated when used as part of a combination regimen with saquinavir in protease inhibitor-experienced, HIV-infected patients.

Analysis of 24-week data from a randomized, active-controlled, blinded study, including 85 patients (A1424-009) compared the safety, efficacy, and tolerability of dual protease inhibitor (PI) therapy of atazanavir/saquinavir regimen or ritonavir/saquinavir regimen after virologic failure on a PI regimen. Patients were randomized to receive 400 mg or 600 mg of atazanavir once-daily with 1,200 mg of saquinavir once-daily or 400 mg of ritonavir twice-daily with 400 mg of saquinavir twice-daily, plus two nucleoside analog reverse transcriptase inhibitors.

Patients enrolled in the atazanavir/saquinavir arm experienced rapid and durable suppression of HIV RNA versus baseline. Groups randomized to receive once-daily doses of 400 mg and 600 mg reporting week-24 mean HIV RNA level changes of at -1.28 (n = 29) and -1.17 (n = 22) respectively compared to -150 (n = 13) in the patients who received 400 mg of ritonavir and 400 mg of saquinavir, both twice a day.

Overall, patients receiving atazanavir/saquinavir experienced no change or a decrease in fasting triglyceride and total cholesterol levels, while those receiving ritonavir/saquinavir experienced marked and sustained elevations in triglyceride and total cholesterol levels. Currently available PI therapy is associated with dyslipidemia, including increased total cholesterol and triglyceride levels, which may be linked to increased cardiovascular risk.

Frequently reported adverse events, including diarrhea and nausea, were seen more frequently in the ritonavir/saquinavir arm versus the atazanavir (400 mg)/saquinavir arm: diarrhea (43% vs. 31%, respectively); nausea (43% vs. 9%). The rate of discontinuation for those patients in the atazanavir/saquinavir arm was 21% and 25%, respectively, for the atazanavir (400 mg)/saquinavir and atazanavir (600 mg)/saquinavir arms; the rate of discontinuation for patients in the ritonavir/saquinavir arm was 43% (Haas, D., et al. 41st ICAAC Abstracts: Addendum 2001, p13)

Recombinant Human Erythropoietin (Epoetin alfa; Procrit®; Ortho Biotech)
A more effective once-weekly dosing schedule of epoetin (40,000 U) was as effective as a three times weekly (100 U/kg) dosing schedule in increasing hemoglobin levels and improving quality of life, with comparable safety and tolerability.

In this multicenter study, 174 HIV-infected patients with hemoglobin levels of less than 12 g/dL while receiving antiretroviral therapy were randomly assigned to receive either epoetin alfa 100 U/kg three times weekly (83 pts) or epoetin alfa 40,000 U once weekly (91 pts) for 16 weeks, both administered subcutaneously, with treatment aimed to normalize hemoglobin levels and improve quality of life.

An interim analysis of the 16-week data demonstrated that the mean change in hemoglobin from baseline to end of study period in the once weekly group was 2.8/dL ( 1.99 and 22.4 g/dL ( 2.4 in the three times a week group. A significant improvement was noted in both hemoglobin levels and quality of life in both a study groups at eight weeks that was maintained until the end of the study. There were no significant differences between the once-weekly or three times weekly treatment regimens in either hemoglobin levels or quality of life at the last measurement. Both methods of epoetin alfa administration were well tolerated in this trial (Grossman, H., et al. 41st ICAAC Abstracts 2001, p322).

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