Emergence of Drug Resistance in HIV Patients on First-line HAART: A Systematic Review of Clinical Trials

By Ronald Baker, PhD

The development of HIV with multiple resistance mutations in individuals receiving combination antiretroviral therapy (HAART) is associated with treatment failure and increased mortality. Understanding the risks of emerging resistance to first-line therapy is important for patients in both wealthy and resource-poor settings.

DRUG RESITANCE MODEL

Drug resistance is a major problem in HIV infections. If patients do not adhere perfectly to their drug regimen, the virus rapidly eliminates its vulnerability. Once it has evaded one drug combination, others are less likely to work as well.

In the present study, published in the September 1, 2008 issue of Clinical Infectious Diseases, researchers undertook a systematic review of clinical trials of adults receiving first-line HAART that consisted of 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) combined with either a non-nucleoside reverse-transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI).

The primary outcome measures of the study were incidences of mutations that conferred resistance to key drugs (NRTIs, NNRTIs, or PI) at week 48.

Results

• This review included 7970 patients in 20 clinical trials with 30 treatment arms.

• Virological failure at 48 weeks occurred in 4.9% of NNRTI recipients compared with 5.3% of boosted PI recipients.

• The M184V mutation in the HIV reverse transcriptase -- conferring resistance to the NRTI lamivudine (Epivir) -- occurred in 35.3% of patients who started NNRTI-based HAART, compared with 21.0% who received a boosted PI.

• For the K65R reverse transcriptase mutation -- conferring multi-NRTI resistance -- the respective incidence rates were 5.3% and 0.0% in patients treated with regimens that did not contain zidovudine (AZT; Retrovir).

• Resistance to the third agent occurred in 53% of patients receiving a NNRTI and 0.9% of those receiving a boosted PI.

In conclusion, the study authors wrote, "Initial therapy with PI/ritonavir-based regimens resulted in less resistance within and across drug classes."
"This finding," they added, "is of particular significance for the developing world, where rates of resistance to NRTIs and NNRTIs at 48 weeks are much higher than has been seen in both cohorts and clinical trials in well-resourced countries."

Discussion

The findings of this study are interesting. "Although the absence of PI mutations at the time of viral rebound during PI/ritonavir treatment can be explained by the high genetic barrier of these drugs, this does not explain the lack of resistance to coadministered drugs -- particularly the NRTI lamivudine," wrote the authors. "We speculate that, because [boosted PIs] retain activity despite low-level emergence or preexistence of NRTI-resistant species, then such resistant species will remain suppressed."

The authors noted that it is important to appreciate that resistance at the time of virological failure is not the only factor to consider when choosing an initial HAART regimen. "Coformulation, simplicity of administration, price, drug interactions (particularly with tuberculosis therapy), and toxicity and adverse events are all important considerations and will differ between different patient populations," they wrote.

Further, they emphasized that it is important to keep in mind that the rate of virological failure was low in both the NNRTI and boosted PI groups, which demonstrates the excellent efficacy of all the regimens evaluated in this study.

Treatment of HIV Patients in Resource-poor Countries

The authors stated that it is important to address the issues of drug resistance and initial HAART in the context of the 9 million HIV patients in resource-poor countries who needed treatment by 2006 according to World Health Organization (WHO) guidelines. Only 3 million of these individuals are receiving HAART, the authors said, and nearly all are using NNRTI-based regimens [1].

Unfortunately, rates of virological failure at 48 weeks in resource-poor settings are almost double those seen in the clinical trials reported in this study, with much higher rates of resistance to NNRTIs (>90%) and NRTIs (>70% for lamivudine resistance and up to 10% for thymidine-associated mutations [TAMs] and the K65R mutation) at the time of virological failure [2,3].

The authors surmised that the high rates of resistance in developing countries may be due to infrequent monitoring of viral load and CD4 cell count, which could lead to prolonged viremia before changing therapy.

"We have demonstrated that use of [boosted PIs] leads to lower rates of resistance to key components of second-line therapy" -- namely, lamivudine, didanosine (ddI; Videx), tenofovir (Viread, also in the Truvada and Atripla coformulations), and abacavir (Ziagen, also in the Epzicom and Trizivir coformulations), stated the authors.

Furthermore, they noted, resistance to the boosted PI itself is a rare occurrence as opposed to NNRTIs, for which the genetic barrier to resistance is low. "Therefore," the researchers stated, "The former agents [boosted PIs] may be more appropriate for use in resource-poor settings, where drug supplies are frequently erratic and where patients may continue to use failing regimens for longer periods of time."

Some studies indicated that ritonavir-boosted PIs may also result in significantly greater increases in the CD4 cell count compared with NNRTIs [4], "and this could be important in the developing world, where HAART is initiated for patients with very low CD4 cell counts," wrote the authors.

Finally, they pointed out that generic versions of ritonavir-boosted PIs are now available, and recommended that their use in first-line regimens should be assessed as part of a global public health approach to the use of HAART.

Division of Infection and Immunity, University College London, London, UK; Pharmacology Research Laboratories, University of Liverpool, Liverpool, UK; Centre for Infectious, Health Protection Agency, UK; SEARCH, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

8/26/08

Reference
R Gupta, A Hill, AW Sawyer, and D Pillay. Emergence of drug resistance in HIV type 1-infected patients after receipt of first-line highly active antiretroviral therapy: a systematic review of clinical trials. Clinical Infectious Diseases 47: 712-722. September 1, 2008.

Other Citations
1. World Health Organization, UNAIDS, UNICEF. Towards universal screening: scaling up priority HIV/AIDS interventions in the health sector. 2008.

2. L Ferradini, A Jeannin, L Pinoges, and others. Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment. Lancet 367:1335-1342. 2006

3. MR Kamya, H Mayanja-Kizza, A Kambugu, and others (Academic Alliance for AIDS Care and Prevention in Africa). Predictors of long-term viral failure among Ugandan children and adults treated with antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes 46:187-193. 2007.

4. SA Riddler, R Haubrih, AG Rienzo, and others. Drug resistance at virological failure in a randomized, phase III trial of NRTI-, PI- and NNRTI-sparing regimens for initial treatment of HIV-1 infection (ACTG 5142). XVI International AIDS Conference. Toronto. August 2006. Abstract THLB0204.