Back HIV Treatment Approved HIV Drugs

Approved HIV Drugs

STARTMRK Trial Shows Raltegravir (Isentress) Works as Well as Efavirenz (Sustiva) in Treatment-naive HIV Patients

The first approved integrase inhibitor, raltegravir (Isentress), suppressed HIV viral load as well as efavirenz (Sustiva) over 48 weeks in the STARTMRK trial, a Phase 3 study of previously untreated patients. Participants taking raltegravir, however, experienced fewer drug-related adverse events.

As reported in the August 3, 2009 advance online edition of The Lancet, STARTMRK (sponsored by Merck) enrolled 566 participants from 67 research centers on 5 continents between September 2006 and June 2008.

Eligible patients had HIV RNA > 5000 copies/mL and no evidence of baseline resistance to efavirenz, tenofovir (Viread, also in the Truvada and Atripla coformulations), or emtricitabine (Emtriva). At baseline, 53% patients had viral load < 100,000 copies/mL and 47% had a CD4 count of 200 cells/mm3 or less.

Participants were randomly assigned in a 1:1 ratio to receive either 400 mg raltegravir twice-daily or 600 mg efavirenz once-daily, both in combination with 300/200 mg tenofovir/emtricitabine once-daily. To make sure the study was blinded, patients in the raltegravir arm also received placebo tablets matching efavirenz, while those in the efavirenz arm received raltegravir-matching placebos.

The primary efficacy endpoint was achievement of HIV RNA < 50 copies/mL at week 48, with a margin of non-inferiority of 12%.


  • In a 48-week non-completion = failure analysis, 86.1% of patients in the raltegravir arm and 81.9% in the efavirenz arm achieved HIV RNA < 50 copies/mL.
  • The difference in efficacy was 4.2%, thereby meeting the criteria for raltegravir non-inferiority.
  • The average time to achieve viral suppression, however, was significantly shorter for patients in the raltegravir arm compared with the efavirenz arm (P < 0.0001).
  • Mean changes in CD4 count from baseline to week 48 were 189 cells/mm3 in the raltegravir arm and 163 cells/mm3 in the efavirenz arm (P = 0.0184)
  • Patients in the raltegravir arm experienced significantly fewer drug-related clinical adverse events -- including central nervous system symptoms -- than those taking efavirenz (44.1% vs 77.0%; P < 0.0001).
  • Serious drug-related clinical adverse events occurred in less than 2% of patients in both arms.
  • Fewer laboratory-associated adverse events were recorded in the raltegravir arm compared with the efavirenz arm, but the difference did not reach statistical significance.
  • Patients taking raltegravir experienced small increases in total cholesterol, LDL ("bad") cholesterol, HDL ("good") cholesterol, and triglycerides, but changes were significantly higher for efavirenz recipients.

Based on these findings, the study authors concluded, "Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48."

"Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients," they continued.

In their discussion, the researchers explained that non-inferiority of raltegravir "was not solely due to the higher number of discontinuations in the efavirenz group than in the raltegravir group."

"Both regimens had consistent efficacy across all baseline prognostic and stratification factors, including patients with high viral loads or low CD4 cell counts," they added

They also noted that more patients taking raltegravir reached undetectable HIV RNA levels by weeks 2-16 (studies typically do not report response prior to 24 weeks), but the clinical significance of this early response is not clear.

Virological failure was rare in both treatment groups, the researchers stated. Of the 8 patients in the raltegravir arm who experienced virological failure with > 400 copies/mL and an HIV integrase gene that could be analyzed, half had mutations known to confer raltegravir resistance.

A smaller Phase 2 study comparing similar regimens (but using lamivudine instead of emtricitabine) found that both raltegravir and efavirenz produced sustained viral suppression though 144 weeks (78% vs 76% < 50 copies/mL, respectively).

Emory University School of Medicine, Atlanta, GA; Orlando Immunology Center, Orlando, FL; Universita Vita-Salute San Raffaele, Milan, Italy; University of California at Davis, Sacramento, CA,; Centro de Referencia e Treinamento DST/AIDS, Sao Paulo, Brazil; Northstar Medical Center, University of Illinois at Chicago, Chicago, IL; Merck Research Laboratories, North Wales, PA.



JL Lennox, E DeJesus, A Lazzarin, and others (for the STARTMRK investigators). Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. The Lancet. August 3, 2009 (Epub ahead of print).

GlaxoSmithKline Meta-analysis Does Not Show Elevated Cardiovascular Risk Associated with Use of Abacavir

Since the 2008 Conference on Retroviruses and Opportunistic Infections, researchers have presented conflicting findings concerning the association between use of abacavir (Ziagen, also in the Epzicom and Trizivir combination pills) and increased risk of cardiovascular events.

As reported in the May 1, 2009 Journal of Acquired Immune Deficiency Syndromes, an analysis of more than 50 clinical trials conducted by abacavir manufacturer GlaxoSmithKline (GSK) did not find an increase in heart attacks or other cardiovascular events.

At CROI 2008, researchers with the large D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) study reported that recent use of abacavir was associated with an unexpected 90% increase in the risk of myocardial infarction (MI), with the increase being most pronounced in individuals with underlying cardiovascular risk factors and diminishing after the drug was discontinued.

Similarly, at the International AIDS Conference the following summer, investigators with the large SMART treatment interruption trial reported that abacavir was associated with an increased risk of MI, stroke, and other cardiovascular events, as well as elevated levels of certain biomarkers of inflammation.

After the D:A:D results were first reported, GSK researchers performed an analysis of the company's past clinical studies to see if they could find a similar "signal" linking abacavir and cardiovascular disease. Results were first reported in part at the 2008 International AIDS Conference.

Using the GSK HIV Data Repository, the investigators compiled data from 52 company-sponsored clinical trials, encompassing all phases of drug development, in which adult participants received at least 24 weeks of combination antiretroviral therapy (2 pediatric studies were excluded from the analysis); 36 of these studies were randomized, including 12 trials in which 3263 patients were randomly assigned to receive abacavir versus a control drug or placebo.

In total, these trials included 9502 HIV positive adults who received abacavir (accounting for 7641 person-years [PY] of follow-up) and 4672 patients who did not take the drug (accounting for 4267 PY). About 60% were treatment-experienced, while 40% were treatment-naive. Overall, most participant (82%) were men, the median age was 37 years, and 10% had a prior AIDS diagnosis; in studies with available race/ethnicity data, 58% were white, 24% were black, and 14% were Hispanic.

The researchers searched adverse event reports for terms related to coronary artery disease (CAD), including coronary artery atherosclerosis or occlusion, myocardial ischemia or infarction, acute MI, angina pectoris, and unstable angina. In addition, they reviewed all fatal adverse events due to any cause.


  • Baseline demographics and HIV disease characteristics -- including lipid and glucose levels -- were similar in abacavir recipients and patients not exposed to abacavir.
  • MI rates were statistically similar for patients exposed to abacavir and those who did not take the drug (intent-to-treat, switch included):
    • Abacavir: 16 MIs; 0.168%; 2.09 per 1000 PY.
    • Non-abacavir: 11 MIs, 0.235%; 2.57 per 1000 PY.
  • Results were consistent when the analysis was restricted to the 12 trials in which participants were randomized to receive abacavir or a control drug/placebo:
    • Abacavir: 4 MIs; 2.15 per 1000 PY;
    • Non-abacavir: 7 MIs; 4.10 per 1000 PY.

"In this pooled summary, we observed few MI events overall and no excess risk of MI with abacavir therapy," the investigators stated.

"It is unclear why results from this data set seem discrepant to the [D:A:D] data set, particularly, as the non-abacavir MI event rate is similar," they added. "Further data are needed to evaluate any association between abacavir and increased risk of MI."

In their discussion, the researchers acknowledged that the total number of study participants may have been too small -- and the follow-up periods too short (typically 24 or 48 weeks) -- to detect an increase in cardiovascular events.

Furthermore, given what was known at the time the studies were designed, they typically did not collect data about cardiovascular risk factors such as blood lipid levels or biomarkers such as C-reactive protein, and did not employ HLA-B*5701 screening for abacavir hypersensitivity.

"Our initial intention was to supplement the descriptive data summaries presented in this article with a more sophisticated multivariate analysis, adjusting for available baseline cardiovascular risk factors," the authors wrote. "However, given the relatively small number of CAD and MI events observed and missing baseline CAD risk factor data for many individuals, this additional work was not viable."

"Whether abacavir has a role in coronary heart disease risk needs further clarification and understanding; however, it is clear that combination antiretroviral therapy overwhelmingly provides substantial survival benefit to patients with HIV," they concluded. "As with all medications, physicians and patients must weigh the risks of HIV disease against the overall benefits and risks of the antiretroviral medicines available."

GlaxoSmithKline Infectious Disease Medicine Development Center, Research Triangle Park, NC; GlaxoSmithKline Global Clinical Safety and Pharmacovigilance and Infectious Disease Medicine Development Center, Middlesex, UK; GlaxoSmithKline Worldwide Epidemiology, Upper Providence, PA.



CH Brothers, JE Hernandez, AG Cutrell, and others. Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects. Journal of Acquired Immune Deficiency Syndromes 51(1): 20-28. May 1, 2009.

CROI 2009: Large Meta-analysis Indicates Antiretroviral Therapy Works as Well for Women as for Men

Since the early years of the AIDS epidemic, researchers and advocates have debated whether HIV positive women benefit as much as men from antiretroviral therapy. Some studies in the early HAART era suggested that women did not fare as well, but many believe this was a reflection of poorer access to care, differences in socioeconomic status, or other factors.

Read more:

CROI 2009: Cancer Incidence in Clinical Trials of Raltegravir (Isentress)

The first-in-class HIV integrase inhibitor, raltegravir (Isentress), was approved by the U.S. Food and Drug Administration in October 2007. During the drug's development, some clinical trials suggested that participants taking raltegravir had a higher rate of malignancies, though this was not confirmed in later studies.

Read more:

Tibotec Applies for Traditional Approval of NNRTI Etravirine (Intelence)

Tibotec announced on February 5, 2009 that the company has submitted an application to the U.S. Food and Drug Administration (FDA) for traditional approval for its NNRTI etravirine (Intelence). The application includes 48-week data from 2 Phase 3 studies known as DUET-1 and DUET-2.

Read more: