With contemporary antiretroviral therapy (ART), the risk of virological failures leading to multiclass resistance has dramatically diminished. However, there are still patients from the pre highly active ART era with multiple-class resistance for whom designing salvage regimens can be very challenging. We report the use of a novel combination – dolutegravir (DTG) and peg-interferon alfa-2a – in a patient with sixtuple-class resistance.
The patient is a 56-year-old man, diagnosed with HIV infection in 1992. After diagnosis, he started treatment with azydothimidine monotherapy and subsequently received dual [nucleoside reverse transcriptase inhibitor NRTI] and triple (NRTI + non-NRTI/protease inhibitor)-drug antiretroviral regimens, as part of routine care and through clinical trials such as TORO (enfuvirtide) , DUET (darunavir/ritonavir)  (randomized to control arm), and raltegravir expanded access. He had been treated with all of the following: dideoxycytidine dideoxyinosine saquinavir, nelfinavir, nevirapine, abacavir, efavirenz, hydroxyurea, lopinavir/ritonavir, amprenavir, enfuvirtide, tipranavir, tenofovir, emtricitabine (FTC), darunavir/ritonavir, etravirine, maraviroc and raltegravir. Unfortunately, he received many of these antiretovirals as functional monotherapy, without other active drugs. He had never achieved sustained virological suppression.
In 2010, while receiving tenofovir difumarate (TDF)/FTC and darunavir/ritonavir and maraviroc, he developed oral candidiasis and wasting. At that time, his CD4+ cell count was 28 cells/μl and the HIV-RNA viral load 1 100 000 copies/ml. Drug resistance genotype testing showed the following as described below.
1. Reverse transcriptase (bold: mutations present in historical genotypes, but not in the last available genotype): M41L, K101E, V108I, V118I, Y181C, M184 V, G190A L210W, T215Y, V179F. According to the Stanford University HIV Drug Resistance Database interpretation algorithm these mutations confer high-level resistance to all nucleos(t)ides and non-nucleoside reverse transcriptase inhibitors.
2. Protease: L10F, V32I, I54L, Q58E, G73S, V82L, I84V, L90M, V11I, M36L, L89V. These mutations confer high-level resistance to all protease inhibitors.
3. Fusion inhibitor resistance: V38M V38A. These mutations reduce enfuvirtide susceptibility by more than 10-fold in site-directed mutants and most clinical isolates.
4. HIV tropism test performed in April 2009 (Trofile): dual/mixed R5/X4 tropic virus. CCR5 inhibitors not active.
5. Integrase: E92Q, N155H, N155I. These mutations confer high-level resistance to raltegravir and elvitegravir and low-level resistance to DTG.
On April 2011, the patient initiated DTG (50 mg b.i.d.) through a named patient/compassionate use program, high-dose darunavir/ritonavir (1000/100 mg b.i.d.), peg-interferon alfa-2a (180 μg weekly) and stavudine (d4T), TDF/FTC and enfuvirtide at standard doses (Table 1). This initial regimen produced a rapid decrease in viral load, but the patient did not achieve complete suppression. For this reason, enfuvirtide was switched to foscarnet after 1 month. Subsequently, the patient achieved virological suppression and foscarnet was stopped. We performed one attempt to switch peg-interferon alfa-2a for oral valaciclovir, but due to a low-level viral rebound valaciclovir was discontinued and weekly peg-interferon alfa-2a reintroduced. Subsequently, for the past 18 months, the patient has been receiving DTG, high-dose darunavir/ritonavir, maraviroc and weekly peg-interferon alfa-2a. This regimen has maintained consistent virologic suppression. The patient has experienced substantial immunological reconstitution with increasing CD4+ cell counts and complete resolution of oral candidiasis and wasting.
We believe that peg-interferon alfa-2a contributed significantly to the antiviral efficacy of the regimen. It is a proven antiviral with activity against HIV . In our case, one attempt to stop peg-interferon alfa-2a, when the patient was virologically suppressed was followed by a low-level viral load rebound. Interestingly, Azzoni et al. have recently reported that administration of peg-interferon alfa-2a to individuals receiving suppressive ART resulted in a sustained control of viral replication in almost half of the patients who interrupted antiretrovirals.
If we consider peg-interferon alfa-2a as an active antiretroviral in the background regimen, then our patient's response is in accordance with the DTG VIKING 3 clinical trial results. In VIKING 3, if the baseline genotype did not harbor the Q148 integrase resistance mutations, and the background regimen had an overall susceptibility score of 1, then the proportion of patients with HIV-RNA less than 50 copies/ml at week 24 was 88% .
We maintain unconventionally high-dose darunavir/ritonavir in light of the high-level resistance, thus expecting residual activity. We also maintain maraviroc with the hope that it retains activity against subpopulations of R5 tropic viruses. These observations remain speculative, as we have not attempted to discontinue each of the components of the regimen. Interestingly, we have been able to stop all inactive nucleos(t)ides.
In summary, our case provides a proof of concept that, in the context of sixtuple-class resistance, the combination of DTG and peg-interferon alfa-2a is able to achieve long-term virologic control if there are no Q148 integrase drug-resistance mutations. This combination merits further study in exceptionally difficult-to-treat cases such as ours.
Conflicts of interest
There are no conflicts of interest.
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