NNRTIs: The Next Generation Approaches

Part II

December 14, 2006

Case Study: Patient JD

JD is a 46-year-old gay male. He first learned of his HIV status in 1994 after a former partner with whom he had been in a three-year relationship discovered that he was HIV infected.

JD felt well when he was first tested for HIV, but he had a CD4+ cell count of 380 cells/mm3 and a viral load of 46,900 copies/mL. This reduced CD4+ cell count suggested that JD might have been infected with HIV for several years. At this point, he sought advice from his physician, who reviewed with JD the standard HIV treatment options available by prescription as well as alternatives available in clinical trials. JD decided to defer treatment for about a year, but he continued to seek input from his physician on treatment advances.

During one visit, JD was newly diagnosed with oral hairy leukoplakia, which was noted to be a minor HIV-associated condition. His CD4+ cell count had also dropped to about 300 cells/mm3, and his viral load was now approximately 63,000 copies/mL. With this one symptom, and small but worrisome changes in his lab tests, JD decided to pursue the best HIV treatment options available at the time in 1995.

JD -- A 46-Year-Old Gay Male
Diagnosed in 1994 Baseline CD4+ cell count: 380 cells/mm3
Viral load: 46,900 copies/mL
1995 Viral load: 63,000 copies/mL
CD4+ cell count: 300 cells/mm3
Begins treatment in a clinical trial: AZT + 3TC
1996 Viral load: 6,200 copies/mL
Adds IDV to AZT + 3TC
1998 Viral load: 800 copies/mL
CD4+ cell count from 400 to 470 cells/mm3
Switched from IDV to NVP and then from NVP to EFV
Viral load drops below 400, but rebounds to 800
1999 Viral load: below 1,200 copies/mL
CD4+ cell count: 383 cells/mm3
Viral load increases to 6,300
2002 Switched to AZT/3TC/ABC + NFV
2004 Viral load: 2,100 copies/mL
CD4+ cell count: above 300 cells/mm3
In December viral load increases to 10,000
2005 Joined clinical trial: placed on etravirine + LPV/r + TDF + FTC
Undetectable viral load (<50) after three months of treatment
CD4+ cell count: more than 500 cells/mm3
After fully reviewing JD's health status, JD's physician recommended that he consider entering a clinical research study that was ongoing at that time. The study was designed to compare four different antiviral strategies, some of which included investigational antiretroviral agents. In this study, JD received a combination of zidovudine (AZT, Retrovir) and lamivudine (3TC, Epivir), and he remained on this regimen for the next year. He felt well and responded well on this combination, achieving a viral load that remained below 5,000 copies/mL for the next year and a CD4+ cell count that increased by about 100 cells/mm3 above his initial entry count of 290 cells/mm3.

In 1996, there was significant enthusiasm for a new approach that proved to be highly effective in clinical trials: the use of triple-drug combination therapy. This approach -- usually based on a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI) -- demonstrated significant improvements over what was seen with the standard approach at that time -- use of only two NRTIs. Based on this information, JD's physician recommended that he consider adding one of the new PIs to his treatment combination. JD agreed to add a third drug at that time, especially since his viral load was still detectable at about 6,200 copies/mL.

JD initially added indinavir (IDV, Crixivan) to his zidovudine + lamivudine regimen. After about 24 months of treatment, he achieved a much better viral load of roughly 800 copies/mL and a CD4+ cell count increase from 400 to 470 cells/mm3. However, despite high fluid intake, he had trouble tolerating this combination due to recurrent kidney stones.

JD then switched from indinavir to nevirapine (NVP, Viramune), while still maintaining the zidovudine + lamivudine combination. This agent was selected to address JD's problem of kidney stones and also because nevirapine was far less complicated to take with fewer dietary restrictions compared to indinavir, thus making it easier for him to be adherent. Unfortunately, JD developed a rash in the first two weeks on nevirapine and had to be switched to efavirenz (EFV, Sustiva, Stocrin). He tolerated the efavirenz regimen fairly well and experienced only temporary and minimal initial side effects, which are commonly seen when starting this antiviral (i.e., he had trouble sleeping and felt somewhat more emotionally "fragile").

At the time, adding a single drug to a stable regimen was not appreciated to be a substandard way to treat HIV infection. Not surprisingly, JD achieved only temporary viral control on this combination. His initial viral load, when starting the NNRTIs instead of indinavir, was 1,200 copies/mL. After the first three months on efavirenz, his viral load did drop to undetectable levels, which at that time was below 400 copies/mL. By month six, however, JD's viral load became detectable at about 800 copies/mL. Over the next year, his viral load remained below 1,200 copies/mL, which was what it was before he started NNRTI treatment, but his viral load then increased to 6,300 copies/mL -- a level similar to the one he had achieved when he was just on zidovudine + lamivudine. In contrast, his CD4+ cell count remained stable at 383 cells/mm3. As such, JD decided to remain on his current regimen, as he felt he was "burning through" too many drug options and wanted to defer additional changes as long as he felt well and his lab tests suggested it was safe to wait before changing therapy.

During the next three years, additional antiretrovirals became available, including new PIs. JD's provider reviewed what was known about these agents and suggested that nelfinavir (NFV, Viracept) was worthwhile to try. This PI was chosen, in part, based on information suggesting that even if nelfinavir did not get the viral load to fully undetectable, future drug treatment options would remain available should resistance to nelfinavir develop. JD agreed to start on this drug, now in combination with a new triple-NRTI, fixed-dose combination tablet -- zidovudine/lamivudine/abacavir (AZT/3TC/ABC, Trizivir) -- that added a new NRTI to the two he was already on. For the next two years, JD did well on this combination, but his viral load was at about 2,100 copies/mL at the end of two years. Although his CD4+ cell count remained above 300 cells/mm3, his provider remained concerned that his viremia would necessitate a future change in regimen. In 2004, his viral load again trended higher, hitting about 10,000 copies/mL by December 2004.

In 2005, a new study opened that offered the chance to try a new NNRTI -- etravirine (TMC125) -- in combination with a standard regimen of NRTIs + lopinavir/ritonavir (LPV/r, Kaletra) + enfuvirtide (T-20, Fuzeon). The comparator arm consisted of an optimized regimen tailored from approved antiretrovirals. After a long discussion about the pros and cons of the study, the provider ordered a resistance test for JD. The test showed that JD had significant resistance to all three classes of drugs -- NRTIs, NNRTIs and PIs. Although he had never taken a boosted PI, JD already demonstrated some resistance to drugs within the PI class.

Based on this, JD joined the study. He was assigned to the etravirine arm, which he received in combination with boosted lopinavir, tenofovir (TDF, Viread) and emtricitabine (FTC, Emtriva). He had very few side effects on his new regimen. After three months of treatment, he received his first viral load test result showing a level below 50 copies/mL. This degree of viral suppression persisted for the next year, and his CD4+ cell count increased to more than 500 cells/mm3.


This case history illustrates one of the major insights into HIV treatment strategies that has been learned over the past decade since triple-drug therapy became the standard. The initial enthusiasm in the three-drug era was based on only a few studies using three drugs. Consequently, there was some confusion between the total number of antiretrovirals a patient was taking and the number of new antiretrovirals started at the time a regimen was switched. After several additional studies were completed, it became increasingly clear that simply adding a third drug, such as an unboosted PI (e.g., indinavir or nelfinavir), to a two-NRTI regimen of a patient with ongoing viral replication was a less successful strategy than starting the patient on at least two new active drugs at the same time. Even if initial viral suppression was observed in a patient who had a third drug added to his or her regimen, this suppression was rarely as durable as that observed when patients started on at least two new active antiretrovirals.

Research studies have been designed in recent years to ensure that people who enroll have the opportunity to start on at least two active drugs so as to be both ethical and reflect the standard medical practice of the current era. As an example, the etravirine study that JD entered was designed so that he could start on boosted lopinavir, enfuvirtide or both, each in combination with etravirine. The comparator arm was also designed so that patients could receive the best combination of active agents among the approved antiretrovirals. This design helped to quickly determine that etravirine produced additional viral suppression in patients switching to a new combination regimen -- results that were statistically superior to even the best available comparator regimens.1 Further studies are underway to assess whether these initially promising results can be replicated in similarly designed studies conducted in large numbers of patients across several countries. Results are expected sometime in 2007.

This is part two of a two-part article. Please click here to read part one.


  1. Cohen C, Steinhart C, Ward D, et al. Efficacy and safety results at 48 weeks with the novel NNRTI, TMC125, and impact of baseline resistance on the virologic response in study TMC125-C223. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0061.

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