Antiretroviral Therapy for HIV: New Data From HIV 8 in Glasgow

Introduction

Nearly 3000 physicians attended the 8th International Congress on Drug Therapy in HIV Infection in Glasgow, Scotland, which has become one of the world's most important periodic conferences that is focused on management of persons with HIV infection. Data from most recent therapeutic trials using approved and experimental antiretroviral (ARV) drugs comprised most of the program. New data on pharmacology of antiretroviral therapy and novel therapeutic strategies were the subject of the remaining presentations.

Treatment of HIV Infection

Antiretroviral Pharmacology

Pharmacogenomics holds promise for individualizing therapy for HIV infection, as therapeutic outcomes are largely influenced by human genetic polymorphisms (Table 1). Drs. David Haas^[1] and Simon Mallal^[2] provided a detailed explanation of the abacavir hypersensitivity reaction (HSR), which develops in more than 80% of persons exposed to abacavir who have the HLA B*5701 allele. However, no more than 40% of suspected abacavir HSRs are ultimately reported in persons who have this allele, suggesting that more than half of these suspected episodes may not be truly abacavir HSRs.^[1,2]

To better understand many of the unanswered questions around this serious adverse effect, the PREDICT-1 study will evaluate the efficacy of baseline HLA testing among nearly 2000 HIV patients, and the results are eagerly awaited. In the meantime, the results of ACTG A5095, a double-blinded US trial that examined the performance of abacavir vs placebo as part of a triple regimen, suggest that in the absence of the HLA B*5701 allele, suspected abacavir HSR often does not follow abacavir exposure but exposure to placebo.^[3] This reinforces that a strong linkage exists between abacavir HSR and HLA B*5701. This association has been further confirmed by skin patch testing, which only can identify cases with prior history of a true abacavir HSR.

Table 1. Genes Associated With Antiretroviral Drug-Related Outcomes

While large interindividual variability exists in plasma levels for most antiretroviral drugs, fluctuations within an individual patient are relatively narrow for antiretrovirals with long half-lives such as nonnucleoside reverse transcriptase inhibitors (NNRTIs) and ritonavir-boosted protease inhibitors (PIs). This characteristic feature allows clinicians to sporadically assess drug exposure through the measurement of trough concentrations.

In HIV patients with chronic liver disease, controversy exists regarding the extent of severe hepatic impairment that may affect drug levels and which as a result may increase the risk for overexposure. Spanish researchers assessed liver fibrosis using elastometry (FibroScan; Echosens; Paris, France), a new noninvasive tool that reliably measures hepatic fibrosis, among 268 HIV/HCV-coinfected antiretroviral-treated patients.^[4] The authors concluded that compensated liver cirrhosis does not significantly influence plasma levels of lopinavir/r or atazanavir/r, but that plasma levels of NNRTIs are increased. This is particularly significant for efavirenz, which is mainly metabolized by the isoenzyme 2B6 of cytochrome P540, which is present in the liver in relatively modest concentrations. This is in contrast with isoenzyme 3A4, the main metabolizer of nevirapine, which is widely distributed in the hepatic tissue (Figure 1).

Figure 1. Hepatic metabolism of nevirapine and efavirenz and preferential compromise of efavirenz metabolism in liver cirrhosis.

Structured Treatment Interruptions

Data from SMART, the largest trial of structured treatment interruptions (STI) conducted to date, were reported earlier this year at CROI.^[5] The premature discontinuation of this study has been a major obstacle to enthusiasm around further study of STIs in the context of HIV. The results of 2 other trials, Trivacan^[6] and DART,^[7] have confirmed the SMART results, with an excess of morbidity and mortality in STI arms compared with control arms. In contrast, the results of the Staccato and Windows^[8,9] studies have shown significant cost savings using STI without deleterious adverse outcomes, as shown in Table 2.

Table 2. Outcome in Major Studies Assessing Structured Treatment Interruptions (STI)

These apparent contradictory results could be somewhat reconciled if we consider that short (4- to 6-month) treatment interruptions may be safe only in patients with CD4+ cell counts > 400-500 cells/mcL.^[9] Also of note, one of the indirect messages of the SMART trial data is that plasma HIV-RNA does matter clinically, because AIDS/death events in the trial were more frequent in patients off therapy across all different CD4 strata.

Ritonavir-Boosted Protease Inhibitors

New Comparative Data. There have been few head-to-head trials of boosted PIs. However, the MaxCmin 1 study with saquinavir/r vs indinavir/r was one of the first of these trials and found that saquinavir/r outperformed indinavir/r, mainly because of side effects and toxicities (kidney stones and dyslipidemia) associated with boosted indinavir. Subsequently, MaxCmin 2 showed that lopinavir/r outperformed saquinavir/r, mainly due to increased side effects associated with the soft-gel formulation of saquinavir. For several years, lopinavir/r has been the standard to which all ritonavir-boosted PIs are measured, and only recently have other boosted PIs been shown to perform at least as well as lopinavir/r. This is the case for fosamprenavir/r (KLEAN study) which showed noninferiority in drug-naive patients compared with lopinavir/r.^[10] More recently, atazanavir/r has shown noninferiority compared with fosamprenavir/r in the ALERT study.^[11]

In Glasgow, investigators presented similar comparative data for saquinavir/r (hard-gel) vs lopinavir/r. The GEMINI study was an international trial in which saquinavir/r 1000/100 mg twice daily was compared with lopinavir/r, in 150 drug-naive HIV patients. (Both boosted PIs were given with coformulated tenofovir + emtricitabine.) The results are summarized in Table 3. While both HIV-RNA suppression and CD4+ cell count gains were comparable between the 2 arms, lipid abnormalities developed more frequently with lopinavir/r than with saquinavir/r.^[12]

Table 3. Results: GEMINI Study

* P < .01
** P < .05

There are at least 2 other studies that are comparing ritonavir-boosted PIs and which will soon be reported -- one comparing darunavir/r vs lopinavir/r (Artemis study) and another comparing atazanavir/r vs lopinavir/r (BMS 138).

Tipranavir. Resistance to tipranavir has been a matter of controversy for a long time. Preliminary data led the drug's manufacturer to suspect that 4 protease mutations at codons 33, 82, 84, and 90 (then so-called UPAMs, or universal protease-associated mutations) were the main determinants of tipranavir resistance. On the basis of this information, the RESIST trials were designed. These are the largest therapeutic studies conducted to date in multiple antiretroviral class-experienced patients. More than 1500 patients were included in RESIST 1 and 2; subjects with HIV with greater than 2 UPAMs were excluded.

Subsequently, however, it became clear that mutation L90M did not affect tipranavir susceptibility, a finding that has somewhat complicated the interpretation of RESIST results, and particularly the efforts to build a genotypic score for this drug. A recent report has shown up to 16 protease mutations that influence tipranavir susceptibility.^[13] In Glasgow, researchers presented data from a small study that suggested that only 6 protease mutations (L33F, I47V, I54A/M, V82T, I84V) confer resistance to tipranavir when 2 or more of these mutations are present.^[14]

The experience using tipranavir/r among nearly 4000 patients in North America and Western Europe in the compassionate use program was also presented in Glasgow.^[15] This population did not have resistance restrictions. At 12 months, the median reduction in plasma HIV-RNA was 1.8 log₁₀ copies/mL and the median CD4+ cell increase was 93 cells/mcL. Less than 20% of patients experienced adverse events leading to treatment discontinuation.

Finally, the results of study BI 1182.33 were presented by Dr. David Cooper.^[16] This was a dose-ranging, multicenter trial in which 562 drug-naive patients were randomized to receive tenofovir and lamivudine with either tipranavir/r 500/200 mg twice daily (TPV-200), tipranavir/r 500/100 mg twice daily (TPV-100), or lopinavir/r. At 48 weeks in the intent-to-treat analysis, the percentage of patients with HIV-RNA < 50 copies/mL was 65.8%, 66.7%, and 69.2%, respectively. Median CD4+ cell counts increased similarly in all 3 arms. At 48 weeks, the TPV treatment groups were non-inferior to the comparator arm. However, the TPV-200 arm was terminated at 48 weeks due to a higher rate of hepatotoxicity. At 60 weeks of follow-up, the TPV-200 arm was no longer non-inferior due to a higher discontinuation rate as a result of a less favorable tolerability profile compared with lopinavir/r.

Darunavir. Tibotec researchers presented pooled analyses of the POWER 1, 2, and 3 trials, in which the predictive value of genotypic and phenotypic baseline resistance to darunavir were assessed.^[17] Table 4 summarizes the main findings.

Table 4. Pooled Data From POWER Studies: Virologic Response (Week 24) to Darunavir as a Function of Baseline Resistance Mutations

The high potency of darunavir was further demonstrated in an analysis in which results were compared of the 3 largest trials conducted to date in triple-class antiretroviral-experienced patients (Table 5).

Table 5. Comparison of Trials Conducted in Triple-Class Antiretroviral-Experienced Patients (ITT Analysis)

Darunavir performed much better than either enfuvirtide or tipranavir/r.^[18] In light of these results, the estimated potency, barrier to drug resistance, and tolerability of the currently available PI can be scored graphically (Figure 2). While the most recently available compounds, including tipranavir and darunavir, seem to outperform the rest, the safety profile of darunavir makes it more attractive relative to tipranavir.

Figure 2. HIV protease inhibitors: potency, tolerability, and barrier to drug resistance.

Antiretroviral Drugs Under Investigation

MK-0518. Most information regarding integrase inhibitors was summarized by Dr. Roy "Trip" Gulick in a symposium organized before the opening ceremony of the conference.^[19] There is no doubt that integrase inhibitors currently represent the most promising new agents for the treatment of HIV infection. Results from phase 2 and 3 clinical trials have proven the potency and good safety profile of MK-0518,^[20-23] a compound being developed by Merck. This drug binds to cDNA in the cytosol of infected cells and blocks strand transfer of the viral genome into the cell's DNA. MK-0518 is active against diverse HIV variants, including HIV-2. Oral absorption is good without any significant effect of food, and it is metabolized in the liver mainly by glucuronidization, as is atazanavir. When these 2 drugs are coadministered, MK-0518 AUC increases by 41%.^[24] In contrast, tipranavir/r reduces MK-0518 AUC by 24%, and this combination should be discouraged.

Data from drug-naive patient populations^[25] have shown the activity of different doses of MK-0518 in comparison with efavirenz. All doses performed equally well and the proportion of patients with
< 50 HIV-RNA copies/mL at 24 weeks was similar with MK-0518 and efavirenz, although the time to achieve virologic undetectability was shorter with MK-0518 than with efavirenz. Moreover, lipid abnormalities were more pronounced with efavirenz than with MK-0518.

Studies conducted in treatment-experienced patients with resistance to all 3 drug classes^[26,27] have shown significantly greater virologic responses among subjects receiving MK-0518 plus optimized backbone therapy (OBT), compared with control subjects only receiving OBT. No differences between 3 distinct doses of MK-0518 (200, 400, and 600 mg twice daily) were found. Merck has decided to move forward with phase 3 clinical trials with a dose of 400 mg twice daily.

With the advent of integrase inhibitors and highly potent PIs such as tipranavir and darunavir, the goal of salvage therapy in patients who have failed all antiretroviral drug classes is now more ambitious: We aim for undetectable plasma HIV-RNA. At least 2 active drugs in the salvage regimen are advised, and the opportunity to use enfuvirtide with one of these new agents usually guarantees this goal. Unfortunately, the expectations around CCR5 antagonists -- another antiretroviral class that has generated substantial interest in the field -- have greatly diminished over the last few months. In fact, no important news regarding the 2 experimental compounds in clinical development (maraviroc and vicriviroc) were presented in Glasgow.

TMC125 (Etravirine). Use of the NNRTI class is limited by extensive cross-resistance among available agents, so new compounds within this class that have activity against NNRTI-resistant viruses have been eagerly awaited. Tibotec designed TMC125 to fill this gap, and preliminary data derived from early trials confirmed expectations regarding its potential utility for patients with NNRTI-resistant virus. However, the results of study TMC125-C227,^[28] which were presented for the first time in Glasgow, raised serious concerns about the activity of the drug in patients who have failed other NNRTIs.

This phase 2 trial enrolled 116 PI-naive patients who had failed a first-line NNRTI-containing regimen. Subjects were randomized to receive 2 NRTIs plus either TMC125 (n = 59) or an investigator-selected PI (n = 57). The study was prematurely discontinued when it became clear that responses in the TMC125 arm were much worse than those in the PI arm. Tibotec has argued that most patients recruited in this trial carried viruses with more resistance mutations than would be expected for first-line failures (due to their recruitment in countries such as Thailand and South Africa, where no second-line regimens are widely available to switch to). However, it was striking that response to TMC125 was transient even for patients with only 1 or 2 NNRTI resistance mutations.^[28] Moreover, the presence of K103N or 181C did not predict response to TMC125, in contrast with prior reports that had highlighted that K103N might only slightly compromise TMC125 activity. The results of phase 3 trials such as the DUET study are awaited with much interest, since they will definitively show the performance of this drug in triple-class antiretroviral-experienced patients.

Treatment of HCV Coinfection in Patients With HIV

Approximately one third of HIV-infected patients also have chronic hepatitis C. This figure, however, is higher among subjects infected parenterally, such as hemophiliacs and intravenous-drug users, and lower among persons infected through sexual contact. There are 2 reasons to prioritize the treatment of chronic hepatitis C in this population. First, progression to end-stage liver disease occurs faster in the coinfected population. Second, the risk for hepatotoxicity with the use of antiretrovirals is increased in subjects with underlying chronic hepatitis C. Unfortunately, HCV response rates have been lower in trials conducted in coinfected patients, in comparison with results seen in HCV-monoinfected individuals. Whether this is due to HIV itself or to prescription of lower doses of ribavirin in most trials conducted in coinfected patient populations is unclear.

The final results of the PRESCO trial were presented in the late-breaker session at Glasgow.^[29] This was a prospective, multicenter, open-label comparative trial. It enrolled a total of 389 HCV/HIV-coinfected patients with CD4+ cell counts > 300 cells/mcL and elevated aminotransferases who had not previously been exposed to interferon received pegylated interferon alfa-2a (180 mcg per week) plus ribavirin (1000 mg daily, if body weight < 75 kg; 1200 mg daily, if body weight > 75 kg). Patients with HCV genotypes 1 and 4 were treated for 48 or 72 weeks, while patients with HCV genotypes 2 and 3 were treated for 24 or 48 weeks.

Overall, 61% of patients were infected by HCV genotypes 1 or 4, and 67% had serum HCV-RNA > 500,000 IU/mL. In an ITT analysis, sustained virologic response (SVR) was achieved by 49.6%, significantly higher in HCV genotype 2/3 than HCV genotype 1/4 patients (72.4% vs 35%; P < .0001). Furthermore, the SVR was higher in patients allocated to extended vs shorter treatment arms (53% vs 31% for HCV-1/4 and 82% vs 67% for HCV-2/3), although a high drop-out rate in the extended treatment arm precluded definitive conclusions. Premature treatment discontinuations due to serious adverse events occurred in 8.2% of patients. Infection with HCV genotype 2/3, lower baseline HCV-RNA, and HCV-RNA < 50 IU/mL at week 12 were independent predictors of SVR in the multivariate analysis.

PRESCO is the largest trial conducted thus far in coinfected patients that used pegIFN plus ribavirin. The use of 1000-1200 mg/day of ribavirin was relatively safe and provided SVR in nearly half of coinfected patients. Therefore, weight-based ribavirin dosing should now be recommended in the HIV setting, and didanosine coadministration should always be avoided. This is true for HCV genotypes 1 and 4 as well as for HCV genotype 3. (Note: No data to date for genotype 2.) Furthermore, the risk for anemia will clearly be reduced by avoiding zidovudine coadministration with this HCV therapy.

Figure 3 summarizes the main results of 3 trials conducted in HIV-negative and HIV-positive patients, in which the impact of using low, flat doses of ribavirin (800 mg daily) is compared with weight-based ribavirin dosing.

Figure 3. Chronic hepatitis C in 3 pivotal trials: SVR using pegylated interferon plus ribavirin.

References

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2. Mallal S. Drug hypersensitivity in the setting of HIV: pathogenesis and management. Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract PL9.1.
3. Gulick R, Ribaudo H, Shikuma C, et al. Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA. 2006;296:769-781.
4. Barreiro P, Rodriguez-Novoa S, Labarga P, et al. Influence of the stage of liver fibrosis on plasma levels of antiretrovirals in HIV patients with chronic hepatitis C. Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract PL6.2.
5. El-Sadr W, Neaton J, for the SMART Study Investigators. Episodic CD4-guided use of antiretroviral therapy is inferior to continuous therapy: Results of the SMART Study. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infection; February 5-8, 2006; Denver, Colorado. Abstract 106LB
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15. Hoen B, Towner W, Opravil M, Soriano V, Kraft M. The Aptivus compassionate use program (CUP): safety and efficacy data from 3,920 patients in the clinic. Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract P162.
16. Cooper D, Zajdenverg R, Ruxrungtham K, Chavez L. Efficacy and safety of two doses of tipranavir/ritonavir versus lopinavir/ritonavir-based therapy in antiretroviral-naive patients: results of BI 1182.33. Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract PL13.4.
17. De Meyer S, Vangeneugden T, Lefebvre E, et al. Phenotypic and genotypic determinants of TMC114 (darunavir) resistance: POWER 1, 2 and 3 pooled analysis. Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract P196.
18. Hill A, Miralles D, Vangeneugden T, Lefebvre E. Durability of HIV RNA endpoints in treatment-experienced patients: analysis of POWER, RESIST and TORO trials. Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract P31.
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21. Grinsztejn B, Nguyen BY, Katlama C, et al, and the Protocol 005 Study Team. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 160LB.
22. Markowitz M, Nguyen B-Y, Gotuzzo F, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment -naive HIV-1 infected patients. Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Ontario, Canada. Abstract THLB0214.
23. Teppler H, Azrolan N, Chen J, et al. Differential effect of MK-0518 and efavirenz on serum lipids and lipoproteins in antiretroviral therapy (ART)-naive patients. Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, California. Abstract H-256a
24. Mistry C, Wenning A, Merschman S, et al. Atazanavir and ritonavir increase plasma levels of MK-0518. Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract P291.
25. Markowitz M, Nguyen B-Y, Gotuzzo F, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients. Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Ontario, Canada. Abstract THLB0214.
26. Grinsztejn B, Nguyen B, Katlama C, et al. Potent efficacy of MK-0518, A novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus: 24-week data. Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, California. Abstract H-1670b.
27. Grinsztejn B, Nguyen BY, Katlama C, et al, and the Protocol 005 Study Team. Potent antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections; February 5-8, 2006; Denver, Colorado. Abstract 160LB.
28. Woodfall B, Vingerhoets J, Peeters M, et al. Impact of NNRTI and NRTI resistance on the response to the regimen of TMC125 plus two NRTIs in Study TMC125-C227. Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract PL5.6.
29. Nunez M, Miralles C, Berdun MA, et al. The PRESCO trial: role of extended duration of therapy with pegylated interferon alfa-2a plus weight-based ribavirin dose in 389 HCV/HIV co-infected patients. Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract PL13.1.