Transmitted resistance to HIV integrase strand-transfer inhibitors: right on schedule

Abstract

Transmitted drug resistance (TDR), the primary acquisition of an HIV variant already resistant to antiretrovirals, impacts approximately 15% of all new infections in the United States. Historically, from the time initial agents in the reverse transcriptase, protease, and entry inhibitor classes were introduced, it took three to five years before the first case reports of TDR appeared. With the description of the first two cases of transmitted integrase stand-transfer inhibitor resistance, it is only a matter of time before the prevalence of TDR affecting this newest antiretroviral class reaches a level warranting baseline resistance testing for all patients entering care.

Of the estimated 56,000 individuals with new HIV infections each year in the United States (U.S.),[1] approximately 8,000 will acquire viruses resistant to at least one antiretroviral (ARV) at baseline.[2] For these patients, their care providers, and public health, the presence of transmitted drug resistance (TDR) poses a number of challenges.

Resistant variants persist for long periods in both the blood[3, 4] and the genital tract[5], increasing the potential for forward transmission among the undiagnosed or untreated. Individuals with TDR seem to have steeper declines in CD4 counts in the first year after infection[6], which may impact immunologic recovery later. Once engaged in HIV care, pre-existing resistance restricts available first-line ARV options and may force providers to select alternative regimens with less favorable dosing intervals or side effect profiles. Adherence may suffer as a result, placing patients at increased risk for accumulating additional resistance mutations over time. Finally, although patients with resistant viruses are benefitting from new ARV classes introduced over the past several years, the current ARV drug development pipeline is relatively limited.

One of the new products from that pipeline is raltegravir, the prototype integrase strand-transfer inhibitor (InSTI) that earned Food and Drug Administration (FDA) approval in 2007. Its safety profile, tolerability, and potency when paired with tenofovir/emtricitabine[7] prompted the inclusion of this combination as a preferred first-line regimen in the U.S. Department of Health and Human Services (DHHS) adult HIV treatment guidelines in 2009.[8] This decision is further supported by studies demonstrating an extremely low prevalence of mutations associated with raltegravir resistance in treatment-naïve patients.[9, 10] Unlike the recommendation to pursue baseline genotypic resistance testing of reverse transcriptase (RT) and protease, the DHHS guidelines specifically noted that pre-treatment integrase resistance testing was not necessary – at least not yet.[8]

With the first two documented cases of transmitted InSTI resistance reported in this issue of Antiviral Therapy,[11, 12] it is only a matter of time before that recommendation changes. But how soon after the introduction of a new ARV class can one expect to see significant circulating resistance? And just how much time do we have before the prevalence of transmitted InSTI resistance reaches a threshold that makes pre-treatment testing necessary? Some historical perspective may help us answer these questions (Table 1).

Table 1.

Date of first clinical trial publication, U.S. Food and Drug Administration (FDA) approval, and initial report of transmitted drug resistance (TDR) for selected antiretrovirals

Year	Antiretroviral class and agent					Event
	NRTI	NNRTI	PI	EI	InSTI
1986	ZDV					Yarchoan, et al. publish first clinical trial [33]
1987	ZDV					FDA approval [34]
1993	ZDV					Erice, et al. report TDR [13]
		NVP				Cheeseman, et al. publish first clinical trial [17]
1995			SQV			Kitchen, et al. publish first clinical trial [21]
			SQV			FDA approval [34]
1996		NVP				FDA approval [34]
1997		NVP				Imrie, et al. report TDR [18]
1998			SQV			Hecht, et al. report TDR [20]
2002				ENF		Kilby, et al. publish first clinical trial [35]
2003				ENF		FDA approval [34]
2006					RAL	Markowitz, et al. publish first clinical trial [36]
2007					RAL	FDA approval [34]
				ENF		Peuchant, et al. report TDR [37]
2010					RAL	Young, et al. and Boyd, et al. report TDR [11, 12]

EI, entry inhibitor; ENF, enfuvirtide (T-20); FDA, US Food and Drug Administration; InSTI, integrase strand-transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; RAL, raltegravir; SQV, saquinavir; ZDV, zidovudine

The first published report of TDR came in 1993, when a young man who presented with acute HIV infection was started on single-agent zidovudine but failed to have any significant response following three months of treatment. After it was learned that one of his likely source partners was receiving zidovudine, retrospective analysis of pre-treatment samples demonstrated the presence of T215Y/F mutations in RT, conferring resistance to the drug.[13] Six years of widespread zidovudine monotherapy following its FDA approval in 1987 led to a high prevalence of resistance among potential transmitters, and up to 10% of seroconversions harbored T215 mutations in select cohorts between 1988 and 1994.[14] Within a decade of the introduction of the class, TDR involving the nucleoside RT inhibitors (NRTIs) was stably high and ranging between 9 and 42%[15, 16].

Only four years elapsed between initial clinical studies of nevirapine, the first non-nucleoside RT inhibitor (NNRTI), in 1993[17] and the first report of NNRTI-associated transmitted resistance in 1997. The HIV-uninfected male partner of a patient on zidovudine-nevirapine dual therapy developed symptoms of primary HIV infection and was found to have K70R, A98G, and Y181C mutations in RT, identical to those in the donor.[18] By 2000, the prevalence of NNRTI-associated mutations among treatment-naïve patients reached 13%.[19]

Protease inhibitor (PI) transmitted resistance trailed the introduction of the class by only three years; primary infection with HIV resistant to NRTIs and PIs was initially described in 1998.[20] The source patient in that case report had an extensive prior treatment history, including all available NRTIs and PIs (saquinavir, ritonavir, and indinavir). It took five years from saquinavir’s introduction in 1995[21] to reach a PI TDR prevalence of 8-9%.[19, 22]

It is important to consider, however, that the population dynamics of resistance today are arguably very different from what they were at the time these studies demonstrated such rapid increases in the frequency of TDR. Before the advent of highly active ARV therapy (HAART), incompletely suppressive mono- or dual-therapy regimens left large portions of the HIV-infected population living chronically with detectable, drug-resistant viremia. Given the relationship between viral load and the likelihood of transmission[23], this large “reservoir” of circulating resistance supported multiple introductions of ARV resistance into the uninfected population over time. With the effective and durable virologic suppression afforded by contemporary HAART regimens, the majority of patients on therapy have low or undetectable viral loads – leading to a broadly reduced risk of forward transmission. Longitudinal data on the impact of lowered “community” viral load on HIV incidence support this hypothesis[24, 25], as do trends in observed TDR prevalence over time. Levels of primary resistance appear to have peaked between 2000 and 2002, with a slight decline and subsequent stabilization to the present day.[26, 27]

That the first cases of transmitted InSTI resistance come only three years after raltegravir’s FDA approval is therefore somewhat disconcerting. Certainly this short time span could be artifact; broader availability and application of routine pre-treatment resistance testing and greater awareness of TDR could have led to heightened vigilance and more aggressive screening. But it is also possible that its appearance reflects our ongoing failures in secondary prevention efforts among people living with HIV – especially the treatment-experienced. Clear associations exist between poor adherence and transmission risk behaviors,[28, 29] and multiple studies implicate small numbers of highly risky patients with resistant viruses as potentially being responsible for a disproportionately large amount of TDR.[30-32]

Thus, the current reports of transmitted InSTI resistance by Young and Boyd are important milestones as we advance toward a better understanding of HIV resistance and the optimal approach to patients entering care. We are now officially on the clock, waiting for the point at which the prevalence of integrase mutations among treatment-naïve patients rises to a level that warrants routine baseline resistance testing. In the meantime, these cases clearly support the addition of InSTI resistance testing for patients presenting to care with higher-than-expected baseline levels of RTI and PI mutations, and for those whose risk histories place them in contact with source patients having ARV treatment experience.

With the history of TDR as a guide, the next several years offer us the opportunity to both actively monitor for increasing InSTI resistance and to improve our understanding of the epidemiology of TDR. Despite the large and growing number of papers on TDR prevalence worldwide, precious few make any attempt to determine what factors are associated with the acquisition of resistant HIV. If we were able to uniformly collect sociodemographic and behavioral data on cases prospectively, we might parlay those findings into effective prevention messages designed to reduce the incidence (and, eventually, the prevalence) of transmitted resistance.