Editor's Note: This article is Part 2 of a two-part series featuring clinical coverage and analysis of the XIV International AIDS Conference. The Editor wishes to gratefully acknowledge the contributions of Michelle E. Roland (University of California, San Francisco) and Mike Youle (Royal Free Center for HIV Medicine, London).
Although delegates to the XIV International AIDS Conference, held July 7-12, 2002, in Barcelona, were greeted with a healthy dose of encouraging news around clinical issues usually expected at this biennial conclave, there was in fact a dearth of the groundbreaking data to which many have become accustomed in the post-highly active antiretroviral therapy (HAART) era. Still, what data were presented in this seaside Catalonian city are of significance as HIV/AIDS-treating physicians deal with how best to sequence antiretroviral agents in increasingly complicated regimens, emerging antiretroviral toxicities, as well as where new antiretroviral agents fit into an increasingly complex treatment equation.
Franco Maggiolo and a team of his colleagues from the Ospedali Riuniti in Bergamo, Italy, presented on a treatment option called selective salvage therapy (SST), an innovative approach to the management of heavily pretreated patients. SST is a genotype-driven antiretroviral treatment that is rapidly adjusted in response to the emergence of new viral populations so that continually adaptive selective pressure is applied. In a 24-month pilot study, 34 patients with extensive previous exposure to antiretroviral therapy underwent SST. Viral load was measured every two months, and the therapy was modified according to the findings of genotypic testing in patients with HIV RNA >10,000 copies/ml. Combination antiretroviral therapy was limited to four or fewer drugs.
The median HIV RNA was maintained between 3,560 and 10,787 copies/ml throughout the study. Therapeutic adjustments were made on an average of 3.0 occasions per patient, and each regimen was maintained for a mean of 6.1 months. Mean CD4 counts increased from 239 cells/mm3 at baseline to 323 cells/mm3 at 24 months (p<0.02). Only two patients experienced clinical progression of HIV disease, and nine patients experienced drug-related adverse events. SST tailored according to the predominant viral strain may be associated with favorable clinical and immunologic responses in heavily pretreated patients and may allow recycling of previously used drugs as major viral populations express mutations not previously observed.
Other studies presented in Barcelona provided evidence that the combination of lopinavir/ritonavir (LPV/r) is gaining popularity as a component of salvage therapy in heavily pretreated patients. In a study by Carmen de Mendoza and colleagues at Instituto de Salud Carlos III, Madrid, Spain, 137 patients with previous exposure to all three classes of antiretrovirals who were failing their current regimen were treated with LPV/r in combination with a nucleoside reverse transcriptase inhibitor (NRTI). The mean HIV RNA and CD4 count prior to the initiation of LPV/r was 4.04 log 10 copies/ml and 285 cells/mm3, respectively.
At six months, a significant virologic response -- defined as >1 log reduction in HIV RNA and/or HIV RNA <500 copies/ml -- was achieved in 61 percent of the patients. At nine months, 58 percent of the patients in the study had achieved a significant virologic response. The mean increase in CD4 cells at six and nine months was 75 and 85 cells/mm3, respectively. Triglyceride levels increased a mean of 70 mg/dl after the start of LPV/r but cholesterol levels remained stable. HIV RNA levels were held to less than 500 copies/ml in 88 percent of the patients with less than five protease inhibitor (PI) resistance mutations at baseline and in 48 percent of those with more than five PI mutations (p<0.001). Combination treatment with LPV/r was generally well tolerated.
Another presentation focused on the use of "mega-HAART," a salvage regimen containing LPV/r + PI + two NRTIs with or without a non-nucleoside reverse transcriptase inhibitor (NNRTI). Miguel Torralba and his colleagues from the Palacio Hospital 12 de Octubre, Madrid, found that the addition of a second PI to LPV/r and an NRTI was associated with significant reductions in viral load and acceptable toxicity in patients who had already been heavily treated. In Torralba's study, 25 highly antiretroviral-experienced patients with documented resistance to all three classes of antiretrovirals received a "mega-HAART" salvage regimen containing LPV/r + PI + two NRTIs with or without an NNRTI. The second PI was saquinavir (SQV) (60 percent), amprenavir (APV) (28 percent), or nelfinavir (NFV) (12 percent). Treatment was guided by prospective genotypic analysis at baseline in all patients. The median viral load and CD4 count at baseline was 16,180 copies/ml and 200 cells/mm3, respectively.
In an on-treatment analysis, 41 percent of the patients in the Madrid study achieved HIV RNA <50 copies/ml at 28 weeks. The median reduction in HIV RNA at 28 weeks was 0.80 log (p=0.001), and 64 percent of the patients showed less than a 0.5 log decrease in HIV RNA at 28 weeks. The median increase in CD4 count at 28 weeks was 64 cells/mm3. Toxicities requiring temporary cessation of therapy were observed in only two patients, and there were no significant increases in hepatic enzyme, triglyceride, or cholesterol levels.
A growing body of evidence suggests that phenotypic and genotypic testing are critical adjuncts to the management of highly treatment-experienced patients, and presentations at Barcelona added to this evidence. Donna Mildvan and her colleagues at the Beth Israel Medical Center, New York, looked at 24 heavily pretreated patients who began taking abacavir (ABC) and at least one additional drug as part of a salvage regimen. The number of HIV protease and reverse transcriptase genotypic resistance mutations and phenotypic drug susceptibility scores (PSS) were measured retrospectively in plasma samples stored at baseline. At baseline, the mean HIV RNA was 5.38 log 10 copies/ml, and 20 patients had four or more resistance mutations.
When the baseline HIV RNA and number of resistance mutations were included in the predictive model, only the baseline HIV RNA predicted the viral load response at week 8 (p<0.05) and only the number of resistance mutations predicted the response at week 24 (p=0.014). When the baseline HIV RNA and PSS were included, each was predictive of the response at week 8 (p<0.05), but only the PSS predicted the response at week 24 (p=0.043). At week 24, HIV RNA was lower in patients whose antiretroviral therapy had been stopped for a mean of three months prior to the start of salvage therapy (mean: 3.18 log 10 copies/ml) than in those who were on treatment at the time of initiation of salvage therapy (mean: 4.77 log 10 copies/ml) (p=0.05).
Resistance to antiretroviral agents is a problem even when patients are good about taking their medications. Non-adherence to prescribed regimens increases the rate at which HAART is ineffective in HIV-infected patients. Providing a viable option in such situations, Hernando Knobel and his colleagues at the Hospital del Mar, Barcelona, found that a simplified salvage regimen containing three NRTIs produced favorable outcomes in a cohort of heavily non-adherent patients whose previous HAART regimen had failed. The study group was comprised of 50 patients considered severely non-adherent (by self-report, they had taken less than 50 percent of prescribed doses in the previous three months or withdrawn from therapy entirely) and who were failing HAART containing two NRTIs and a PI. All patients were switched to a combination of ABC and 3TC/ZDV (Combivir) twice daily and later switched to ABC/3TC/ZDV (Trizivir) twice daily. All patients had HIV RNA >5,000 copies/ml and none of the patients had mutations associated with resistance to NRTI or PI at the start of salvage therapy.
At 24 weeks, the mean HIV RNA decreased 1.6 log 10 copies/ml and the mean CD4 count increased 124 cells/mm3. Overall, 66.5 percent of the patients achieved HIV RNA levels at less than 500 copies/ml in on-treatment analysis, as did 44 percent in intention-to-treat (ITT) analysis. Treatment-related adverse events were observed in 22 percent of the patients. Not surprisingly, adherence was greater with the salvage regimen than with previous HAART: 50 percent of the patients reported satisfactory adherence (taking more than 90 percent of prescribed drugs) with the twice-daily salvage regimen.
Two PI-sparing combination antiretroviral regimens were compared with a standard PI-containing regimen in a study led by Remko van Leeuwen at the International Antiviral Therapy Evaluation Center in Amsterdam. In this study, 298 antiretroviral-naive patients were treated with stavudine (d4T) and didanosine (ddI) and either nevirapine (NVP), lamivudine (3TC), or indinavir (IDV). The median CD4 count and HIV RNA at baseline were 406 cells/mm3 and 4.3 log 10 copies/ml, respectively.
After 48 weeks, the proportion of patients who showed <500 copies/ml of HIV RNA was just above half in each of the three treatment groups. Of patients taking NVP, 58.4 percent were at this level of HIV RNA per milliliter, while the number was 58.7 percent of those taking 3TC, and 57 percent of those on IDV. The proportion of patients with more than 49 copies/ml of HIV RNA was significantly less in the 3TC group (28.4 percent) than in those treated with NVP (55.1 percent) or IDV (44.0 percent). Patients in the NVP group experienced a smaller increase in the absolute CD4 count than did those in the other two groups. The incidence of serious adverse events was similar in all three groups. High-density lipoproprotein (HDL) cholesterol levels increased 40 percent in the NVP group, while the total HDL cholesterol ration decreased 6 percent in the NVP group and increased 25 percent in the IDV group.
Evidence of the long-term efficacy of triple NRTI therapy in severely immunosuppressed patients emerged in a study by Motserrat Lonca and colleagues at the Gatell Hospital Clinic, Barcelona. In this study, 68 patients with CD4 counts <200 cells/mm3 received triple therapy including two NRTIs and NVP or efavirenz (EFV). The study group included 23 patients (34 percent) with AIDS-defining illnesses, 38 (59 percent) with CD4 counts <100 cells/mm3, and 52 (76 percent) with HIV RNA appearing at a rate of 100,000 copies/ml. The time from the diagnosis of HIV infection to the beginning of antiretroviral therapy was less than 12 months in 22 patients (32 percent).
At 24 months, ITT analysis showed that 86 percent of the patients had CD4 counts that were >200 cells/mm3 and all of the patients in the study had HIV RNA levels at <200 copies/ml. Similar trends in CD4 counts and HIV RNA levels were observed in the NVP and EFV groups. Only five patients (7 percent) discontinued NVP or EFV due to adverse effects.
EFV-based HAART proved comparable to PI-based HAART in severely immuno-compromised patients in a study led by Federico Pulido of the Hospital La Paz, Madrid. The study tracked 214 treatment-naive patients with advanced HIV infection and CD4 counts of <100 cells/mm3 who underwent treatment with either EFV- or PI-based HAART. At 12 months, the proportion of patients who achieved CD4 counts <100 cells/mm3 was 70 percent in the EFV group and 58 percent in the PI group, and the proportion who achieved HIV RNA levels <400 copies/ml was 78 percent in the EFV group and 55 percent in the PI group. After adjusting for baseline CD4 count, concurrent treatments, clinical status, and other variables, the use of EFV and PI was not associated with significantly different immunologic or virologic outcomes at 12 months. During the first year, EFV was discontinued in 13 patients (14 percent) and PI was discontinued in 30 patients (24 percent) (p=0.09).
The long-term durability of the triple NRTI regimen ABC/3TC/ZDV was examined in a study by a team from the J.W. Goethe-Universitat in Frankfurt headed by Peter Gute. A group of 128 antiretroviral-naive patients were started on triple combination therapy with ABC/3TC/ZDV and followed for a median of 20 months. Study endpoints included adding or switching to a different class of antiretroviral agent or to an NRTI regimen without ABC or treatment interruption without reinitiating a triple NRTI regimen containing ABC.
Overall, 83 patients (65 percent) were still on an ABC-containing triple NRTI regimen after a median of 20 months. Only 17 patients (13 percent) switched to a new class of antiretroviral agent and five patients (4 percent) switched to a different triple NRTI combination without ABC. A total of 23 patients (18 percent) stopped therapy after the initial regimen and did not restart treatment. Based on therapy changes, ABC/3TC/ZDV proved effective and well tolerated for long-term use in antiretroviral-naive patients.
The ability to maintain virologic control while switching from PI- to either NVP-or EFV-based combination therapy was demonstrated in a study by Patricia Patterson and her colleagues at Cahn Fundacion Huesped, Capital Federal, Argentina. The study looked at 120 NNRTI-naive patients who were switched from a PI-based regimen to an NVP- or EFV-based regimen without changing background NRTIs. All patients had evidenced HIV RNA counts at <50 copies/ml within six months of switching.
Patterson's presentation also showed that potential complications could be kept to a minimum over time. At 36 weeks, the proportion of patients who experienced virologic failure (two HIV RNA measurements >500 copies/ml) or treatment-limiting toxicity was 14 percent in the NVP group and 12 percent in the EFV group (p=NS). The median increase in CD4 count from baseline was 2 cells/mm3 in the NVP group and 21 cells/mm3 in the EFV group. Lipid profiles improved in the NVP group and remained unchanged in the EFV group.
Bodily pain increases following the initiation of HAART and is related to immunologic and virologic parameters, reported Ségolène Duran and colleagues at INSERM U379, in Marseille, France. The finding was based on a study of 1,045 patients initiating PI-based HAART who completed standardized quality of life surveys at baseline and after 12 months of treatment. Treatment adherence was measured by self-report and by comparison of immunologic and virologic parameters determined at baseline and after 12 months.
Following the initiation of HAART, the mean score for bodily pain was the only component of the well-being survey to show significant deterioration (p=0.04). In contrast, mean scores for physical functioning, general health perception, social functioning, role limitations due to physical and emotional problems, vitality, and general mental health improved significantly at one year after HAART initiation. In a multivariate analysis, mean changes in bodily pain scores were independently related to lower bodily pain scores at baseline. Higher levels of bodily pain at 12 months were associated with patients older than 35 years, baseline CD4 counts >200 cells/mm3, female gender, lower baseline HIV RNA, loss of body weight, and self-reported non-adherence. The initiation of HAART may be associated with worsening of bodily pain in patients with favorable immunologic and virologic profiles at baseline.
Dyslipidemia is a frequent complication of HAART, but the incidence of coronary artery disease (CAD) and other cardiovascular complications in patients receiving HAART is unknown. In a study by Giorgio Barbarini and colleagues at the University of Pavia, Italy, 1,551 treatment-naive patients started HAART with or without PI and were followed for up to three years. The study endpoint was the cumulative incidence of CAD in terms of recently developed angina, unstable angina, and fatal or nonfatal myocardial infarction (MI).
Overall, 21 percent of the patients in the PI group and 3 percent of those in the non-PI group developed dyslipidemia and associated metabolic alterations during follow-up. The cumulative annual incidence of CAD was 9.8 per 1,000 in the PI group and 0.8 per 1,000 in the non-PI group (p<0.001), and the cumulative annual incidence of MI was 5.1 per 1,000 in the PI group and 0.4 per 1,000 in the non-PI group (p<0.001). Stepwise logistic regression analysis revealed that the incidence of CAD was primarily associated with dyslipidemia, lipodystrophy, and smoking and was independent of age, gender, and CD4 count.
Alterations in bone mineral density (BMD) are significantly more common in HIV-positive Caucasian women receiving HAART than in their HIV-negative counterparts, reported Barbara Smith who led a study at the University of Alabama at Birmingham, in the United States. A group of 20 HIV-positive women who received HAART for one year were compared with a matched control group of HIV-negative women. Study measurements included total fat mass, fat free mass, subcutaneous and visceral abdominal adipose tissue, and bone mineral content.
Despite similarities in age, race, body mass index, and menopausal status, HIV-positive women had nearly twice the amount of visceral abdominal adipose tissue (mean: 10,416 cm2) as the HIV-negative women (mean: 5,543 cm2) (p=0.0009). The amount of subcutaneous abdominal adipose tissue was greater in the HIV-positive women than in the HIV-negative women, but the difference was not statistically significant. Among all patients, BMD as measured by dual energy x-ray absorptiometry was similar in both groups. Among Caucasian women, BMD was significantly lower in the HIV-positive group (mean: 2,178 g) than in the HIV-negative group (mean: 2,411 g) (p=0.03).
Evan Collins and colleagues from the University of Toronto, Canada, examined lipodystrophy and its effects on health-related quality of life and treatment adherence. Lipodystrophy severity was assessed in 83 patients receiving HAART who completed standardized self-report measures for depression, anxiety, self-esteem, medication adherence, and overall symptoms. The mean duration since diagnosis of HIV infection was 10 years, the mean duration of antiretroviral use was seven years, the mean HIV RNA was 8,600 copies/ml, and the mean CD4 count was 534 cells/mm3.
There were moderate correlations between lipodystrophy severity and quality of life measures related to physical and psychosocial functioning. In cross-sectional sampling, however, lipodystrophy severity had no apparent influence on depression, anxiety, self-esteem, or self-reported medication adherence. Hypertrophy was shown to have a more negative effect on patients; it was associated with psychological distress and worry. The impact of lipodystrophy severity on quality of life was greater in younger patients, suggesting that advanced age may mitigate some of the negative effects of lipodystrophy on quality of life. Patients' self-assessment of the severity of their lipodystrophy correlated well with clinician ratings.
The observation that patient characteristics may influence some of the effects of HIV-related lipodystrophy on quality of life was bolstered by the findings of a study by Jordi Blanch and other researchers at the Hospital Clinic Universitari, Barcelona. In comparison with a group of 66 HIV-positive patients without lipodystrophy, 84 patients with lipodystrophy were older, had received antiretroviral therapy for a longer period of time, and reported a poorer physical status. Surprisingly, lipodystrophy itself was not found to influence overall quality of life. In comparison with their counterparts without lipodystrophy, those with lipodystrophy who were homosexual, unemployed, or had a history of psychiatric illness showed greater impairment on quality of life sub-scales related to psychological well being.
Changes in body fat distribution after three years of HAART are similar in patients receiving NRTI-, NNRTI-, and PI-based combination therapy, reported Baiba Berzins and colleagues from the Northwestern University Medical School in Chicago. The unexpected finding emerged in an analysis of preliminary data from the Atlantic Study, an ongoing, prospective, randomized, international trial of d4T/ddI administered in combination with 3TC, NVP, or IDV in 298 treatment-naive patients. Changes in body fat distribution were determined in a subgroup of 69 patients at baseline and every 24 weeks thereafter during treatment.
Accumulation of fat in the abdomen, neck, or breasts was observed in 23 percent, 9 percent, and 5 percent of those receiving 3TC, NVP, or IDV (p=0.15), respectively. Loss of fat in the arms, legs, face, or buttocks was observed in 27 percent of patients in both the 3TC and NVP groups and in 19 percent of those taking IDV (p=0.78). The mean ratios of visceral and subcutaneous to total adipose tissue were similar in patients with and without body fat redistribution. The results of abdominal CT and whole body DEXA scans revealed no significant differences in body fat between the groups.
Given these statistics, it is no surprise that resistance was heavily discussed at the XIV International AIDS Conference (as well as at the preceding XI International HIV Drug Resistance Workshop held July 2-5, 2002, in Seville, Spain). In fact, there was a great amount of discussion about ways to improve our understanding how resistance impacts on the efficacy of antiretroviral agents.
Among the issues up for discussion in Barcelona was that of hypersusceptibility, a phenomenon where the acquisition of resistance appears to make the virus more, rather than less, susceptible to certain antiretroviral agents. Richard Haubrich and colleagues of the University of California, San Diego, examined the prevalence, associated factors, and clinical significance of NNRTI hypersusceptibility (NNRTI-HS). They enrolled 177 patients without prior NNRTI therapy who were failing (HIV RNA >400 copies/ml) stable antiretroviral therapy and administered ViroLogic phenotype assay, HIV RNA, and CD4 counts before changing to a new NNRTI-containing regimen at baseline. NNRTI-HS was defined as a fold change in IC50 of less than 0.4 (patient compared to reference control). The mean baseline HIV RNA was 4.1 log 10 , the CD4 count was 322 cells/mm3, and the patients had been treated for an average of 41 months. NNRTI-HS appeared to be common: EFV-HS was 24 percent, DLV-HS was 17.5 percent, and NVP-HS was 20 percent.
EFV-HS was associated with duration of previous NRTI use (p<.001), number of NRTI agents (p=.002), use of ZDV (p=0.04), and reduced susceptibility to ZDV and ABC (fold change in IC50 >5.0 compared to control) (p<.005). The mean change in HIV RNA through six and 12 months after starting a new NNRTI-based regimen was greater in the 21 patients with NNRTI hypersusceptible virus compared to the 77 patients without HS (at month 12) (p=.023). CD4 cell increases were also greater for patients with HS virus. Thus the phenomenon of hypersusceptibility appears to offer a significant advantage to the host.
In an attempt to evaluate the impact of combining both resistance assays in a single report (PhenoSense GT), genotype and phenotype tests were performed on approximately 200 patients participating in a pilot program. Genotypic interpretations were based on an updated algorithm reflecting state-of-the-art knowledge. Discordance was defined for drugs with a fold-change in IC50 over the PhenoSense HIV assay cut-off but scored as genotype sensitive (PR/GS), or vice versa (PS/GR). Within the cohort 85 percent of the patients had two or more treatment failures and PT/GT discordance was observed in 75, 54, 33, and 22 percent of samples for at least one, two, three, or four agents, respectively.
After accounting for mixtures at resistance-associated positions, only ddI (29 percent), ddC (20 percent), 3TC (14 percent), ABC (14 percent), and APV (11 percent) had discordance rates over 10 percent. The majority of samples showed PT/GT discordance for at least two of 15 drugs. This combination approach to resistance testing may hopefully expand the picture for clinicians while not increasing the complexity of interpreting test results.
Susan Sufka and colleagues at the Duke University Medical Center in Durham, North Carolina, examined replicative capacity in patients with discordant CD4 count and viral load responses. Nine of 30 HIV-infected patients on PI-based HAART who had viral load of 500 to 5,000 copies/ml, and CD4 count of >200 cells/mm3 increasing over more than two years were compared with successfully treated patients (viral load <50 copies/ml, CD4 count >200 cells/mm3 increasing over more than two years). Despite high-level drug resistance, CD4 cells continued to increase in the discordant group and viral load remained partially controlled. Diminished HIV replicative capacity persisted. Evolution of viral and immunologic responses was observed during the additional year of follow-up suggesting that replicative capacity may be a major factor related to the success of a regimen in the face of persistent HIV viremia.
Two studies examined the relationship to virologic outcome of phenotypic resistance at baseline in subjects taking ritonavir boosted indinavir regimens. A research team from Stanford University, in Palo Alto, California, and the Kaiser Permanente Medical Center in Santa Clara, California, examined 88 subjects with a phenotype taken prior to commencing IDV/ritonavir (RTV). Median duration of prior antiretroviral therapy was 50 months, median number of prior PIs was two, median baseline CD4 count was 184 cells/mm3, and the median baseline viral load was 4.6 log 10 c/ml. IDV/RTV doses were twice daily and varied IDV 400 to 800 mg and RTV 100 to 400 mg. The median and mean IC50 fold changes for IDV were 1.87 and 17.2, respectively (range 0.35 to >178). Virologic responses by IDV fold change categories were calculated using available data through 24 weeks for all patients, and appeared to diminish with increasing baseline IDV phenotypic resistance, although some subjects appeared to respond even with baseline IDV phenotypes of up to 25 fold changes.
The second study from Rafael Campo of the University of Miami examined IDV IC50 of plasma viruses from 73 patients with PI failure (median two prior PIs) using the PhenoSense assay, and compared these with virologic responses to subsequent IDV/RTV (800 mg/200 mg twice daily)-containing regimens. Plasma HIV RNA suppression was scored at HIV RNA nadir and after 24 weeks of therapy. Adjusting for covariates that may have affected suppression did not change the relationship between baseline phenotype and outcome. IDV/RTV-based regimens achieved viral suppression in heavily pretreated patients with prior failure of multiple PIs, including IDV. Baseline IDV "resistance" >2.5-fold or >5-fold was not associated with lessened suppression. Although proportionally fewer patients with >10-fold IDV resistance achieved suppression, the difference was not significant.
Zidovudine prophylaxis is recommended to prevent perinatal HIV-1 transmission. Limited data exist on the role of reduced susceptibility to antiretrovirals (viral "resistance") in perinatal transmission. A study was presented in Barcelona that examined its association with reduced susceptibility to ZDV determined by genotypic and phenotypic methods and the agreement between these methods. Stored plasma from baseline and delivery was tested in 24 transmitting and 72 non-transmitting women matched for baseline HIV RNA in PACTG 185 (a 1993-1997 controlled trial of anti-HIV hyperimmune globulin to reduce perinatal transmission in women with CD4 count <500 cells/mm3 on ZDV and given ZDV prophylaxis).
PCR amplifiable sequences of subtype B in 95 women and subtype A in one woman were obtained. ZDV resistance mutations were found in six (25 percent) transmitting and eight (11 percent) control women. Phenotypic ZDV resistance was found in six of 23 (26 percent) transmitters and nine (13 percent) controls. Overall agreement between genotypic and phenotypic methods was 97 percent for identification of presence or absence of ZDV resistance (p<0.0001). Reduced susceptibility to ZDV by either method was found twice as often in transmitting compared with non-transmitting women.
There were new data presented in Barcelona with regard to genotypic resistance testing itself. Data presented included the NARVAL trial, an updated multivariable logistic regression model of predictors of virologic response or failure at 12 weeks. In the French trial, of 541 randomized patients, 39 percent achieved suppression of HIV RNA levels to <200 copies/ml. Among the factors that were significantly associated with virologic success was the prescription of EFV in NNRTI-naive patients (OR 4.37) and randomization to the genotype group (OR 2.13).
The importance of using an NNRTI in salvage regimens in NNRTI-naive patients is a recurring and very important theme. Not surprisingly, NNRTI use appears to play an even more significant role in virologic success than does access to a genotypic resistance test. Nevertheless, this analysis does suggest that there is an additional benefit -- beyond reminding clinicians to include an NNRTI -- afforded by the resistance test itself. Factors associated with lack of virologic response included prescription of NFV in this highly PI-experienced population (OR 0.30), higher baseline viral load (OR 0.37), five or more PI-resistance mutations (OR 0.42), three or more NRTI mutations (OR 0.61), and PI exposure greater than 30 months (OR 0.64). In summary, the virologic benefit associated with the genotype test appears modest compared to the variables related to the extent of antiretroviral experience and the new drugs selected.
There were also data presented in which researchers compared genotyping and phenotyping. Among the two more prominent studies presented in Barcelona was VIHRES, a randomized study comparing the short-term virologic effects of genotypic versus phenotypic resistance testing. One hundred forty-four patients who had failed more than two HAART regimens and had HIV RNA levels >5,000 copies/ml were randomized to receive either a genotype test or a phenotype test, with results of both assessed by a committee of experts, prior to modification of their antiretroviral regimen. At 24 weeks, the proportions of subjects in the genotype and phenotype arms with HIV RNA <200 copies/ml were not statistically significantly different (50 percent and 40 percent, respectively) (p=0.48). Of note, this finding is different from that of the NARVAL study, where the genotype arm was superior to the phenotype arm. It also differs in that a "no-resistance test" control was not included.
The CERT trial compared the outcomes of patients randomized to receive a genotypic resistance test, a phenotypic resistance test, or no resistance test prior to modifications in antiretroviral therapy. No expert guidance was provided. The outcome variable in this study -- time to persistent virologic failure despite a change in antiretroviral therapy -- was different than in all previous studies. Virologic failure was defined as less than 1.0 log 10 copies/ml reduction in HIV RNA by four weeks, failure to achieve HIV RNA of <200 copies/ml four to six weeks after antiretroviral therapy change, an increase in HIV RNA to detectable levels in subjects with previously undetectable HIV RNA, or greater than 0.5 log 10 copies/ml increase from nadir HIV RNA level. If subsequent antiretroviral changes resolved the virologic failure, the subject remained on the study without reaching an endpoint.
Among the 450 study subjects, the median CD4 count was 471 cells/mm3 and the median HIV RNA level was 2.76 log 10 copies/ml. The median follow up was 525 days. Subjects in both the genotype and phenotype arms had a delayed time to virologic failure compared to the no resistance test arm (574 days for genotype, 521 days for phenotype and 478 days for no test); there was no difference in this respect between the genotype and phenotype groups.
Of particular interest is that the genotype interpretation methodology changed over the course of the CERT trial, which to some extent complicates the interpretation of data. Genotypes were initially interpreted with the commercially supplied, rules-based algorithm employed by Virco, and then with Virco's Virtual Phenotype when it became commercially available. Thus, it is not clear if this study should be considered a comparison of genotype versus phenotype testing, or of Virtual Phenotype versus phenotype testing.
Henry Keith and his colleagues at the Hennepin County Medical Center in Minneapolis presented in Barcelona findings from TORO 1 (T-20 vs. Optimized Regimen Only), a multicenter North American study of enfuvirtide in treatment-experienced patients. In this study, 491 patients who had more than six months experience with three classes of antiretroviral agents and HIV RNA measurements >5,000 copies/ml were randomized to optimized background (OB) therapy alone or in combination with enfuvirtide. OB consisted of three to five antiretroviral agents selected on the basis of prior history and genotypic and phenotypic resistance testing. Twice daily doses of enfuvirtide were administered subcutaneously. The median baseline HIV RNA and CD4 count was 5.2 log 10 copies/ml and 80 cells/mm3, respectively.
At 24 weeks, the mean decrease in HIV RNA was 1.70 log in the enfuvirtide group and 0.76 log in the OB group (p<0.0001). The proportion of patients with more than 400 HIV RNA copies/ml at 24 weeks was 37.1 percent in the enfuvirtide group and 16.4 percent in the OB group. The mean increase in CD4 counts at 24 weeks was 76 and 32 cells/mm3 in the enfuvirtide and OB groups, respectively. Injection site reactions were experienced by 98 percent of the patients treated with enfuvirtide, but only 2.8 percent of these patients discontinued treatment for this reason. Of patients receiving enfuvirtide, 11.3 percent withdrew from the study. A similar percentage of patients receiving OB, 10.9 percent, also withdrew.
The second phase III study of enfuvirtide presented in Barcelona, TORO 2, was similar in design to TORO 1. Bonaventura Clotet and colleagues at the Hospital Germans Trias i Pujol in Barcelona offered the results of TORO 2. In this study, 504 patients recruited from 64 sites in Europe and Australia were randomized to enfuvirtide with or without OB. All patients had less than three months of experience with three classes of antiretroviral agents. The median baseline HIV RNA and CD4 count was 5.1 log 10 copies/ml and 98 cells/mm3, respectively. Almost all patients had HIV with five or more primary resistance mutations to the three classes of antiretroviral agents.
At 24 weeks, the mean decrease in HIV RNA was 1.43 log in the enfuvirtide group and 0.65 log in the OB group (p<0.0001). The proportion of patients with HIV RNA levels at <400 copies/ml at 24 weeks was 28.4 percent in the enfuvirtide group and 13.6 percent in the OB group. The mean increase in CD4 counts at 24 weeks was 65 and 38 cells/mm3 in the enfuvirtide and OB groups, respectively. Aside from the injection site reactions, the adverse events profiles were similar in both groups.
Atazanavir (ATV) is a novel once-daily PI currently in phase III clinical development. Preliminary findings presented in Barcelona suggest that ATV may be associated with a low incidence of dyslipidemia and other metabolic abnormalities. A group of 346 patients receiving NFV-based HAART were switched to ATV with d4T and 3TC in a study by Michelle Kiskorna and colleagues, Ingenix, Basking Ridge, New Jersey. At 12 weeks, significant reductions in total and LDL cholesterol and triglycerides and increases in HDL cholesterol were observed. The once-daily PI may be associated with decreased cardiovascular risk and provide a useful option for the simplification of combination antiretroviral therapy.
Extended-release d4T (d4T-XR) administered once daily is well tolerated and exhibits immunologic and virologic activity similar to that of twice-daily treatment with immediate-release stavudine (d4T-IR) when administered in combination with EFV and 3TC, reported Meredith Pugh of Medisolutions, New York. In a multinational, double-blind, placebo-controlled study, 797 treatment-naive patients were randomized to d4T-XR or d4T-IR in combination with EFV and 3TC. The mean baseline HIV RNA and CD4 cell count was 4.8 log 10 copies/ml and 277 cells/mm3, respectively.
After 48 weeks, mean increases in CD4 counts were 187 and 181 cells/mm3 in the d4T-XR and d4T-IR groups, respectively. Virologic responses were similar in both groups, and 4 percent of patients in each group discontinued treatment due to adverse effects. The rate of treatment-related peripheral neurologic symptoms was lower in the patients treated with d4T-XR than in those treated with d4T-IR.
Poly 1:poly C12 U is a biological response modifier that has been shown to augment delayed-type hypersensitivity responses in HIV-infected patients. The mechanism of action of poly 1:poly C12 U is activation of the intracellular antiviral mediators 2-5A synthetase/RNase L, and the compound is currently in phase II of clinical development. In a study reported by William Mitchell and colleagues, Hemispherx Biopharma in Philadelphia, eight treatment-naive patients received poly 1:poly C12 U (400 mg intravenous twice weekly) monotherapy and seven treatment-experienced patients received poly 1:poly C12 U in combination with stable HAART. At study entry, HIV RNA and CD4 counts were greater than 4,000 copies/ml and 400 cells/mm3, respectively, in the treatment-naive patients, and between 500 and 30,000 copies/ml and over 300 cells/mm3, respectively, in the treatment-experienced group.
After 24 weeks, patients receiving poly 1:poly C12 U monotherapy experienced a 0.25 log 10 copies/ml decrease in HIV RNA (p=0.04). The treatment-experienced patients experienced a 0.50 log 10 copies/ml decrease in HIV RNA after a mean of 4.5 months. Adverse events in patients treated with poly 1:poly C 12 U were generally mild and self-limiting, and no adverse changes in blood lipid profiles or glucose metabolism were observed.
The global spread of HIV/AIDS is fueled by poverty, discrimination, and ignorance, but, sadly, even in the absence of major clinical findings that might warrant prioritization of the research agenda, it was unclear what the XIV International AIDS Conference achieved in harnessing greater global action to redress these ills. The foundation of a meaningful global response to the HIV/AIDS pandemic is a balanced approach to research, prevention, and care activities. Without the active involvement of governments and other organizations with the influence and resources to affect global change, what hope can be held for progress in slowing the spread of HIV/AIDS and providing adequate treatment to those already infected? The opportunity was missed in Barcelona, but perhaps the XV International AIDS Conference in Bangkok will be different.
David S. MacDougall is a medical writer in New Jersey. Email: firstname.lastname@example.org.
Back to the October 2002 issue of IAPAC Monthly.