ARV Update

• 48-Week Study Results Show DRV's Staying Power
• Delaying Maternal NVP-Based ART More Effective
• Frequent Methamphetamine Use, Primary NNRTI Resistance

48-Week Study Results Show DRV's Staying Power

By Edwin J. Bernard

The recently-approved protease inhibitor (PI), darunavir (DRV), boosted by ritonavir (RTV) and in combination with an optimal background regimen, continues to show itself to be safe and potent, according to three studies presented at the Frontiers in Drug Development for Antiretroviral Therapies (DART) conference, held December 10-14, 2006, in Cancun, Mexico.^1-3 At 48 weeks, a total of 45% of over 450 POWER 1, 2, and 3 study participants had a plasma viral load below 50 copies/ml, with short- and longer-term side effects and toxicities comparable to most first-line boosted PIs.

POWER 1, 2, 3

Some 24- and 48-week results from all three POWER studies -- have previously been reported, but these new reports include more detailed results, in particular adverse event data.

POWER 1 and 2 were randomized, controlled studies in which 131 highly treatment-experienced participants were randomized to DRV/RTV 600 mg/100 mg twice-daily, and another 124 highly treatment-experienced participants received any other approved RTV-boosted PI along with an optimized background regimen -- which included two or more nucleoside reverse transcriptase inhibitors (NRTIs) and/or enfuvirtide (ENF). POWER 3 was a combination of two open-label, non-randomized, rollover studies comprising a total of 324 highly treatment-experienced participants who received DRV/RTV 600 mg/100 mg twice daily along with an optimized background regimen.

Toxicity and Side Effects

The most commonly reported adverse events in participants on DRV/RTV in all three POWER studies were mild-to-moderate diarrhea, nausea, and headache. A total of 9% of those on DRV/RTV in POWER 1 and 2 discontinued due to adverse events compared with 5% on other RTV-boosted PIs.

In POWER 3, 25% of participants experienced a grade 3 or 4 laboratory adverse event (although not all of these might have been due to DRV/RTV alone). A total of 7% experienced high amylase (a predictor of pancreatitis); another 6% had high triglycerides and/or high blood sugar; 4% had high total cholesterol; and around 3% had unusually high liver function tests. However only 2% discontinued due to adverse events. Although 14% experienced diarrhea and 10% experienced nausea in POWER 3, the investigators say that there was "no [DRV/RTV] dose relationship... observed and there was no clear relationship between...dose and the frequency or severity of [adverse events]."

Triglyceride levels were above normal for all POWER 1 and 2 participants at baseline. By week 48, mean triglyceride levels were 24% lower in those on DRV/RTV and 25% for those on other boosted PIs. Mean low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol levels remained within normal ranges.

Virological Results

At week 48, 45% of the pooled POWER 1,2 and 3 participants had viral loads below 50 copies/ml; and more than 90% who had reached this point at week 24 continued to remain undetectable at week 48.

A total of 62% on DRV/RTV in POWER 1 and 2 (and 61% in POWER 3) had at least a one-log reduction in viral load from baseline at week 48. Furthermore, 73% of POWER 1 and 2 participants on DRV/RTV, and 82% of POWER 3 participants, who had achieved a greater than one-log drop in viral load at week 24 -- but not an undetectable viral load -- maintained or improved their virologic response by week 48.

Efficacy Predictors

Week 48 efficacy was analyzed by various phenotypic and genotypic resistance tests. When examining baseline phenotypic fold change to DRV/RTV undetectable viral load at week 48 was achieved by 54% of participants with a 10-fold or lower change at baseline, compared with 28% and 14% of patients with a 10- to 40-fold change, and a greater than 40-fold change, respectively.

A total of 53% of participants with two or fewer DRV-associated PI mutations achieved an undetectable viral load at week 48, compared with 20% of participants with three or more DRV-associated PI mutations. Similarly, 54% of participants with two or more active NRTIs in their optimized background regimen achieved an undetectable viral load at week 48.

Utility of ENF

In participants with one or more DRV-associated mutations at baseline, ENF made no apparent contribution to potency (62% versus 64% with undetectable viral loads at week 48 in those who used ENF for the first time compared with those who did not use ENF). However, the participants who did not use ENF appeared to be less treatment-experienced than those who did, since they had a higher mean CD4 count and more active NRTIs in their optimized background regimen at baseline (198 cells/mm³ versus 112 cells/mm³, and 41% versus 22% with two or more active NRTIs, respectively).

Enfuvirtide made much more of an impact in those with two or more DRV-associated mutations at baseline. A total of 62% of participants with two DRV-associated mutations who used ENF for the first time achieved an undetectable viral load, compared with 40% who did not use ENF. And 43% of participants with three or more DRV-associated mutations who used ENF for the first time achieved an undetectable load, compared with 14% who did not use ENF.

Real World Experience

A fourth DRV presentation, from an HIV clinic in Houston, found that real world results of DRV/RTV in the drug's Expanded Access Program were similar to -- or even better than -- those of the pooled POWER studies.⁴

Here, 38 individuals (average age 48, mostly white males, two coinfected with hepatitis C virus [HCV]) with limited or no treatment options (on average they had received 11 prior antiretroviral drugs); more than 95% had burned through three or more PIs -- including tipranavir (TPV) for one in three -- and 39% had previously taken ENF. They received twice-daily DRV/RTV 600 mg/100 mg along with a variety of other antiretroviral drugs. Of the 23 who took ENF, 15 had not taken it before.

By October 2006, all had been on DRV for at least 12 weeks, and 23 had used the drug for 24 weeks. At baseline, mean viral load and median CD4 count were 126,775 copies/mL and 144 cells/mm³, respectively.

Nine adverse events were considered "possibly related to" DRV: two mild rashes; one mild bout of nausea; two abnormal (grade 2) liver function tests; one high (grade 2) total cholesterol test; one very high (grade 3) triglyceride test; one increased (grade 2) creatinine level; and one increased (grade 2) total bilirubin. Another two serious events occurred that were considered unrelated to DRV: one ENF injection-related hematoma requiring surgery, and one death.

After 12 weeks, 54% achieved a viral load below 50 copies/mL. At week 24, 11 of the 22 for whom data were reported (50%) were undetectable -- 10 had achieved this by week 12. Total mean viral load reduction at week 24 was 2.17 log₁₀ copies/mL and the mean CD4 count increase was 109 cells/mm³ Of the 22 patients with CD4 data at baseline and at week 24, 42% had CD4 counts below 50 cells/mm³ at baseline. By week 24, 80% had CD4 counts above 100 cells/mm³.

Editor's Note: Reprinted with permission from www.aidsmap.com (first e-published December 21, 2006).

References

1. Ruane P, Gallant JE, Tennenberg A, Spinosa Guzman S. Safety and efficacy of darunavir in combination with low-dose ritonavir: 48-week results from the POWER studies. Frontiers in Drug Development for Antiretroviral Therapies. December 10-14, 2006. Cancun, Mexico. [Abstract 74]

2. Gathe J, De Jesus E, Falcon R, et al. Examination of factors influencing response to darunavir combined with low-dose ritonavir in POWER 1, 2, and 3: Pooled 48-week analysis. Frontiers in Drug Development for Antiretroviral Therapies. December 10-14, 2006. Cancun, Mexico. [Abstract 66]

3. Rinehart AR, Picchio G, de Bethune M-P, et al. Prevalence of darunavir-associated mutations in samples received for routine clinical resistance testing. Frontiers in Drug Development for Antiretroviral Therapies. December 10-14, 2006. Cancun, Mexico. [Abstract 16]

4. Gathe J, Degazon K, Mayberry C, et al. Single-center experience of darunavir (DRV) in 38 HIV-infected adults enrolled in US expanded access program. Frontiers in Drug Development for Antiretroviral Therapies. December 10-14, 2006. Cancun, Mexico. [Abstract 65]

Delaying Maternal NVP-Based ART More Effective

By Keith Alcorn

Women who received single-dose nevirapine (NVP) at the time of childbirth had better outcomes from a NVP-based triple combination antiretroviral regimen if they started antiretroviral therapy (ART) more than six months after delivery, according to results of a study publishing in the January 11, 2007, edition of the New England Journal of Medicine.

Concern about the effectiveness of NVP-based ART for women previously exposed to NVP at the time of delivery centers around the risk that a single dose of the drug may be enough to cause long-lasting resistance. This is because NVP levels can take 10 to 14 days after a single dose to fall below the limits of detection in many women, and throughout this period the potential exists for NVP-resistant virus to emerge.

In order to study the effect of peripartum NVP exposure on subsequent response to NVP-based ART, US researchers from the Botswana-Harvard School of Public Health AIDS Initiative conducted a prospective observational study in Botswana that included 218 postpartum, HIV-infected women who had received NVP or placebo at delivery plus a short course of zidovudine (ZDV) during pregnancy in the previous MASHI study.

Sixty women started NVP-based ART within six months of giving birth, and the remaining women began the regimen after that time had passed. Of the 60 women who started NVP-based ART within six months of giving birth, 24 had received a single dose of NVP during labor, while 36 had received a placebo. (All of the women in the study were given ZDV from 34 weeks into their pregnancies through delivery; similar to NVP, ZDV reduces HIV transmission from mother to child.) Of the women in this group who received a single dose of NVP during labor, 41.7% subsequently experienced virologic failure within a half a year of starting ART -- compared to zero percent among the women in this group who had received placebo during delivery (P < 0.0001). Similar differences were found at follow-up visits one and two years after ART had started.

In contrast, there were no statistically significant differences in failure rates within the women who delayed ART for six months -- regardless of whether they had received a single dose of NVP during labor. This group (and additional women who have joined the study since) continues to be followed to ensure that no differences emerge as the women receive treatment over a longer period of time.

According to the investigators, "these results translate into very clear policy for how to treat AIDS in new mothers who received [NVP] to protect their infants. If you can wait six months to administer NVP-based ART, do so. If not, treat only with combinations of drugs that do not contain NVP or NVP-related drugs. Implementing this policy can improve the health of women who need AIDS treatment."

Advice about NVP-based regimens also applies to efavirenz (EFV)-based regimens, since NVP and EFV are cross resistant.

Treatment response was also measured among 30 infants in the study who received NVP-based ART. More than three-quarters of the 15 infants who were exposed to single-dose NVP as newborns did not respond adequately to the triple-drug treatment (compared with 9.1% of the 15 infants without prior NVP exposure). While these results raise concerns regarding the use of NVP-based ART for infants following single-dose NVP exposure, the group of infants studied was small, and additional data among infants is needed.

The investigators conclude that, "women who need combination ART for their own health during pregnancy should absolutely receive combination ART whenever possible. However, single-dose NVP remains important in preventing mother-to-child transmission of HIV in many locales where it is still the only intervention available. This study provides some important guidance and measured reassurance regarding the timing and effectiveness of NVP-based [ART] for the many women with AIDS who previously received single-dose NVP in labor."

Editor's Note: Reprinted with permission from www.aidsmap.com (first e-published January 10, 2007).

Reference

1. Lockman S, Shapiro RL, Smeaton LM, et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med. 2007; 356(2):135-147.

Frequent Methamphetamine Use, Primary NNRTI Resistance

By Michael Carter

Frequent methamphetamine use is associated with primary resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) in gay men, according to a San Francisco study published in the January 11, 2007, edition of AIDS. The study's investigators speculate that poor adherence to antiretroviral therapy (ART) by gay men on "meth binges" may lead to the development of NNRTI-resistant HIV which is then transmitted to other methamphetamine-using gay men who engage in unprotected sex.

Investigators from the University of California, San Francisco wanted to see if methamphetamine use was associated with primary drug resistance in a cohort of 287 gay men recently infected with HIV. Their study was prompted by the case of the "New York patient" who was thought to have become infected with a highly resistant strain of HIV via unprotected sex under the influence of methamphetamine. In addition, high rates of methamphetamine use have been reported by gay men in the United States, and several American studies have found an association between risky sexual behavior and methamphetamine use among gay men. The investigators therefore believed it was plausible that methamphetamine could be implicated in the transmission of drug-resistant HIV.

All the study participants had been infected with HIV within the previous 12 months. They completed structured interviews to assess their HIV risk behavior and drug use in the six months prior to HIV seroconversion. None of the individuals included in the investigators' analysis was on ART. Genotypic resistance tests were performed to see if the individuals had primary HIV drug resistance.

Over a quarter (83 individuals, 28%) of men reported methamphetamine use in the previous 30 days, and frequent (weekly or more) methamphetamine use was reported by 12% of men. Resistance to at least one antiretroviral drug was present in 77 individuals (26%). The investigators found that men who reported frequent methamphetamine use had a higher prevalence of primary drug resistance (34%) than men who used methamphetamine monthly (21%), or who reported never using methamphetamine (25%).

The investigators, controlling for factors including ethnicity, number of sex partners, and the use of other illicit drugs, then performed further statistical analysis. Frequent methamphetamine use remained significantly associated with resistance to any antiretroviral drug (P = 0.006). No such relationship was established for infrequent use of the illicit drug. The investigators next conducted a set of analyses to see if the use of methamphetamine was associated with primary resistance to any particular class of antiretroviral drug. Controlling for the same factors as in their first analysis, they found a strong association between frequent use of methamphetamine and resistance to NNRTIs (P = 0.03). No association was found between infrequent use of methamphetamine use and NNRTI resistance, or between frequent and infrequent use of the drug and resistance to protease inhibitors (PIs) or nucleoside reverse transcriptase inhibitors (NRTIs).

"Our results ... suggest that methamphetamine may be an important cofactor in the transmission of NNRTI resistance in this population." The authors note that an earlier study found users of methamphetamine disrupted their adherence to ART during "meth binge episodes" lasting 24 to 72 hours. They speculate, "repeated cycles of such behavior could result in the emergence of drug resistance because of spasmodic treatment interruptions." They add that, "the convergence of treatment interruptions and high-risk behavior could be responsible for the high rates of resistance we report here."

Editor's Note: Reprinted with permission from www.aidsmap.com (first e-published January 10, 2007).

Reference

1. Colfax GN, Vittinghoff E, Grant R, et al. Frequent methamphetamine use is associated with primary non-nucleoside reverse transcriptase inhibitor resistance. AIDS. 2007;21(2):239-241.