Not one case of transmission of HIV that is resistant to any of the integrase inhibitor (INI) drugs has been seen in newly-diagnosed patients in a database of resistance tests in California, the ICAAC 2015 conference heard last month.
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 INI resistance would inevitably arise and start circulating in the pool of viruses being transmitted, especially as acquired INI 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 INI resistance.
The first integrase inhibitor, raltegravir (Isentress), was approved in 2007, and since then dolutegravir (Tivicay) has also 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.
US 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 boosted protease inhibitor darunavir/ritonavir.
Integrase inhibitor resistance can arise in situations favouring drug resistance such as insufficient but not zero adherence, or lack of other effective drugs in the combination regimen. In the two pivotal studies of raltegravir, STARTMRK and SWITCHMRK, resistance to raltegravir was found in a third of drug-naïve patients taking raltegravir whose treatment failed and who developed drug resistance, and 60% of treatment-experienced patients - though that only represents four out of seven individuals, and INI 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 INI resistance exacts a price in terms of viral fitness (its ability to replicate).
In the US, just over one in six (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 (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 INI-resistant viruses can happen and has been documented in several studies: the first case was seen in 2009 (Young) and there have been a couple of confirmed reports since. This led to forecasts that INI 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 two 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.”
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 therapy (ART) before and were having resistance screening on diagnosis or when they were to start ART.
The overall prevalence of any drug resistance was 24.9%, or one in four of all viruses transmitted. This was 24% in 2013, 30% in 2014 but fell to 15.9% in 2015.
NNRTI resistance was the most common, at a prevalence of 13%, 23% and 10% in the three years 2013-2015 respectively: NRTI resistance had a prevalence of 10%, 6% and 4.5%; and 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, INI resistance was not that rare and in fact was slightly more common than PI resistance. During the three years the percentage of patients who developed INI 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 NNRTI drugs and a steady 7-8% for the NRTIs.
One striking finding was that far more patients over 50 had transmitted drug resistance, with 38% having NNRTI resistance and even 30% having PI resistance: this was at least six times the rate in patients under 50. In fact the majority of patients over 50 (57%) had some drug resistance compared to only 18% under 30. Resistance to NRTI and NNRTI drugs increased steadily according to the age of the patient.
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 INI 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 Dr Chuck Walworth comments that “Despite predictions to the contrary, the study demonstrates that transmitted drug resistance involving INIs has been and remains surprisingly rare.”
INI 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 INI drugs will be effective for the foreseeable future. However, Dr Walworth commented, the prevalence of HIV resistance to the other three classes of antiretrovirals is still high enough to justify baseline resistance testing at diagnosis or before starting therapy for all patients.
Dr Ben Young, who found the first case of transmitted INI resistance, told Aidsmap: "The study results are particularly important because of the relative paucity of INI resistance screening in most clinic settings; they represent one of the first to report community-level surveillance of INI resistance.
"Failure to detect transmitted INI resistant virus...must be due to both low rates of treatment failure and low replication capacity of INI-resistant virus.
"The results are highly reassuring and further reinforce the potential benefits of integrase inhibitor-based treatments."
Volpe JM, Walworth CM et al. Absence of Integrase Inhibitor Resistant HIV-1 Transmission in the California AIDS Healthcare Foundation Network. ICAAC 2015 conference, San Diego. Abstract no LB3389. 2015.
Young B 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):253-6. 2011.
Hurt CB. Transmitted Resistance to HIV Integrase Strand-transfer Inhibitors: Right on Schedule. Antiviral Therapy 16(2): 137-140. 2011.
