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ICAAC 2015: No Transmission of Integrase Inhibitor-Resistant HIV Seen in California Patients


Not one case of transmission of HIV that is resistant to any of the integrase inhibitor drugs has been seen among newly diagnosed patients in a database of resistance tests in California, according to a presentation at the 55th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)last month in San Diego.

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The reasons for this are unclear, given that integrase inhibitor resistance that arises on treatment is not that uncommon. Because of this, it was anticipated that integrase inhibitor resistance would inevitably arise and start circulating in the pool of viruses being transmitted, especially as acquired integrase inhibitor resistance actually develops rather more frequently than resistance to protease inhibitors -- which does get transmitted.

The researchers commented that more data from a larger patient group was needed to confirm these observations and to find the reason for the apparent rarity of transmitted integrase inhibitor resistance.


The first integrase inhibitor, raltegravir (Isentress), was approved in 2007, and since then dolutegravir (Tivicay) has been approved, and also elvitegravir (Vitekta), though the latter must be taken with a booster drug and is most commonly found in the triple-combination pill Stribild.

U.S. treatment guidelines recommend the use of a regimen containing an integrase inhibitor for people starting antiretroviral treatment. As an alternative, people may start treatment with the protease inhibitor ritonavir-boosted darunavir (Prezista).

Integrase inhibitor resistance can arise in situations favoring drug resistance such as insufficient but not zero adherence, or lack of other effective drugs in a combination ART regimen.

In the two pivotal studies of raltegravir, STARTMRK and SWITCHMRK, resistance to raltegravir was found in a third of drug-naive patients taking raltegravir whose treatment failed and who developed drug resistance, and in 60% of treatment-experienced patients -- though that only represents 4 out of 7 individuals, and integrase inhibitor resistance was not common in either study.

However, it was also noted that once people stop taking an integrase inhibitor, the resistant strains rapidly disappear and resistance-free strains take over, showing that integrase inhibitor resistance exacts a price in terms of viral fitness (ability to replicate).

In the U.S., just over 1 in 6 (17.5%) of HIV viruses diagnosed between 2008 and 2011 had some drug resistance. In terms of classes, depending on site, 3% to 11% had resistance to the nucleoside/nucleotide (NRTI) drugs, 3% to 16% to the non-nucleoside (NNRTI) drugs, and 1.5% to 4.5% to the protease inhibitor (PI) drugs.

We know that transmission of integrase inhibitor-resistant viruses can happen and has been documented in several studies: the first case was seen in 2009 (Young et al) and there have been a couple of confirmed reports since. This led to forecasts that integrase inhibitor resistance was destined to become as common as resistance to other HIV drug classes.

One commentator said in 2011, when the first cases were reported in a journal (Hurt): "With the description of the first 2 cases of transmitted integrase inhibitor resistance, it is only a matter of time before the prevalence of transmitted drug resistance affecting this newest antiretroviral class reaches a level warranting baseline resistance testing for all patients entering care."

This Study

The latest study appears to show that transmitted resistance to integrase inhibitors is not emerging.

In this study the commercial testing firm Monogram Biosciences looked at all the samples of HIV tested for drug resistance at their San Francisco laboratory between March 2013 and June 2015. Patient samples were sent at quarterly intervals from 13 California sites in the AIDS Healthcare Foundation (AHF) network of clinics. There were 1090 samples in all, 339 of which were from patients who had never taken antiretroviral treatment before and were having resistance screening upon diagnosis or when they were about to start ART.

The overall prevalence of any drug resistance was 25%, or 1 in 4 of all viruses transmitted. This was 24% in 2013 and 30% in 2014, but fell to 16% in 2015.

NNRTI resistance was the most common, at a prevalence of 13%, 23%, and 10% in the 3 years 2013 to 2015, respectively. NRTI resistance had a prevalence of 10%, 6%, and 4.5%, respectively, while PI resistance prevalence was 4.4%, 4.4% and 3.4%.

No transmitted integrase inhibitor resistance was observed at all. This is particularly remarkable because when the Monogram scientists looked at acquired drug resistance in people on treatment, integrase inhibitor resistance was not that rare, and in fact was slightly more common than PI resistance.

During the 3 years, the percentage of patients who developed integrase inhibitor resistance while on treatment was 3.4%, 3.9%, and 2.4%, which was roughly double the proportion of patients who developed resistance to PIs. Acquired drug resistance to the NNRTI and NRTI drugs was higher at 12%-19% for NNRTIs and a steady 7%-8% for the NRTIs.

One striking finding was that far more patients over age 50 had transmitted drug resistance, with 38% having NNRTI resistance and 30% having PI resistance; this was at least 6 times the rate for patients under 50. In fact, the majority of patients over 50 (57%) had some drug resistance compared to only 18% of those under 30. Resistance to NRTI and NNRTI drugs increased steadily according to the age of the patient.

Comments and Conclusions

These older patients have never taken ART before, so their higher resistance rates cannot be due to more treatment experience. It is most likely due to more treatment experience in their partners: older patients will tend to have older partners, and some of those partners could be people who have lived with HIV for a long time, have resistance from the old days of substandard therapy, and may be going through a period of treatment failure.

The fact that PI resistance is far higher in over-50s supports this theory, as older partners are more likely to have been on earlier, unboosted PI regimens.

This could explain some of the lack in integrase inhibitor resistance too: integrase inhibitors have only been used in the era when HIV regimens were generally effective, so much less resistance is seen. That does not entirely explain the complete lack of transmission, however.

Researcher Chuck Walworth commented that, "Despite predictions to the contrary, the study demonstrates that transmitted drug resistance involving integrase inhibitors has been and remains surprisingly rare."

Integrase inhibitor resistance needs to be evaluated in a much bigger patient database than 13 AHF clinics and some cases will probably be found. It is good news for HIV therapy, however, as it implies the integrase inhibitor drugs will be effective for the foreseeable future. However, Walworth commented, the prevalence of HIV resistance to the other 3 classes of antiretrovirals is still high enough to justify baseline resistance testing at diagnosis or before starting therapy for all patients.

Ben Young, who found the first case of transmitted integrase inhibitor resistance, told Aidsmap: "The study results are particularly important because of the relative paucity of integrase inhibitor resistance screening in most clinic settings; they represent one of the first to report community-level surveillance of integrase inhibitor resistance."

"Failure to detect transmitted integrase inhibitor resistant virus…must be due to both low rates of treatment failure and low replication capacity of integrase inhibitor-resistant virus," Young continued. "The results are highly reassuring and further reinforce the potential benefits of integrase inhibitor-based treatments."



JM Volpe, O Yang, CJ Petropoulos, and CM Walworth. Absence of Integrase Inhibitor Resistant HIV-1 Transmission in the California AIDS Healthcare Foundation Network. 55th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). San Diego, September 17-21, 2015. Abstract LB3389.

B Young et al. Transmission of Integrase Strand-Transfer Inhibitor Multidrug-resistant HIV-1: Case Report and Response to Raltegravir-containing Antiretroviral Therapy. Antiviral Therapy 16(2):253-256. 2011.

CB Hurt. Transmitted Resistance to HIV Integrase Strand-transfer Inhibitors: Right on Schedule. Antiviral Therapy 16(2):137-140. 2011.