This study found that in our cohort of newly diagnosed, ARV naïve individuals of unknown duration of infection, those who reported using methamphetamine within the 30 days prior to their HIV diagnosis were more likely to have TDR to NNRTI than those who did not. Methamphetamine users do not represent a homogenous group of individuals, in our cohort, those who reported using methamphetamine within 30 days of their HIV diagnosis most likely represented active or on-going users, while those who reported using “methamphetamine ever” but not within 30 days of their diagnosis most likely represented sporadic users. These two groups differ in both the psychosocial reasons for methamphetamine use as well as in the type and frequency of high risk sexual behaviors [2
]. More frequent methamphetamine use has been associated with higher rates of unprotected sexual intercourse, trading sex for money or drugs, and having partners of unknown or serodiscordant HIV status [24
]. But these are risk factors for HIV acquisition, not for TDR [27
Our phylogenetic analyses did not yield evidence of transmission linkage of TDR among methamphetamine users; however, our sample was probably too small to draw firm conclusions through these molecular epidemiology techniques. Despite the lack of statistically significant phylogenetic linkages, the positive association between active methamphetamine use and NNRTI TDR is provocative.
The acquisition of a resistant virus by the recipient partner suggests certain characteristics about the source partner, such as HIV positive status, access to medical care, ARV exposure, and perhaps medication adherence [24
]. Also, active methamphetamine use by recipient partners is most likely associated with methamphetamine use by the source partners [24
]. Taken together, we theorize that active methamphetamine use is associated with acquisition of HIV TDR at multiple levels, as proposed in Fig. (
]. Possibly secondary to cognitive and behavioral changes induced by methamphetamine use or side effects induced by select NNRTI, the source partner may had reduced ARV compliance, leading to evolution of drug resistant mutations [30
]. The lower genetic barrier to resistance to currently available NNRTI, can occur at higher levels of adherence than for the development of resistance to PI [31
]. In particular, Efavirenz can produce a state of long restless sleep, vivid dreams, and nightmares that individuals try to avoid after an episode of methamphetamine use [33
]. Additionally, NNRTI resistance in the source partner may be more likely to be transmitted to the recipient partner than other forms of ARV class resistance because NNRTI resistance-associated mutations have less impact on viral replication capacity [32
]. For example, the common NRTI resistance-associated mutations, M184V and T215F/Y, typically impair HIV replication capacity in the absence of ART [35
]; therefore, these mutations may be more likely to revert to drug susceptible forms [37
] than NNRTI resistance-associated mutations, and may allow these NNRTI mutations to persist for longer after discontinuation of NNRTI selective pressure, increasing the risk of NNRTI TDR [17
]. This is supported by our data where most individuals in our cohort showing NNRTI TDR did not also show NRTI TDR, even though a source partner with NNRTI resistance probably would have also developed NRTI resistance, as these ARV’s are often used together in clinical practice [9
Theoretical model of casual association between active methamphetamine use and transmitted drug resistance (METH = Methamphetamine; ↑ = Increase; ↓= Decrease).
Not knowing the duration of infection in our cohort could be a methodological limitation because any reversion of a drug-resistance mutation to wild-type would cause an underestimation of the prevalence of TDR, and this may occur more frequently in other drug classes [12
]. However, not knowing the exact duration of HIV infection is often the case in most clinical scenarios, and without knowing the duration of infection in our cohort, we still found a rate of HIV TDR comparable to that seen with primary HIV infection [9
], which is entirely consistent with the long duration of TDR, particularly with NNRTI [12
Our findings must be tempered by the following limitations. First, we have no direct information in the source partner. Second, our sample size may not have been sufficiently large to detect associations between methamphetamine use and PI or NRTI TDR. Indeed, based on the observed proportions of PI and NRTI among individuals unexposed to methamphetamine within 30 days prior to HIV diagnosis, our study only had 33% and 70% power to detect an association between metamphetamine exposure and PI and NRTI TDR when the odds ratio was greater than or equal to 3. Although subtle associations could have been missed, a previous report with 300 patients also did not find any association between methamphetamine use and PI or NRTI TDR [16
]. Third, as with all location specific cohort studies, our results cannot be generalized to all individuals with HIV infection because of potentially unique aspects of the location of our cohort [12
Despite these limitations, this study has substantial clinical implications. It reinforces the need for routine resistance testing among individuals newly diagnosed with HIV, particularly recent methamphetamine users, even when the duration of infection is unknown. Furthermore, it questions the clinical practice of prescribing NNRTI-based regimens to individuals with active methamphetamine use. It follows that if the source of the TDR is the source partner and if the recipient partner is actively using methamphetamine so is the source partner [24
], then perhaps PI-based regimens instead of NNRTI should be used to treat HIV infection among individuals who continue to use methamphetamine so as to limit the spread of NNRTI TDR.