Clinical, immunological, and virological outcomes in HIV patients on raltegravir-based salvage therapy.

OBJECTIVES: The objective of the study is to assess the clinical, immunological, and virological outcomes in treatment-experienced HIV patients on raltegravir (RAL)-based salvage therapy.
METHODS: This was a retrospective, observational study of patients with suspected second-line antiretroviral therapy failure who were followed up for at least 6 months, from January 2013 to January 2017, after switching to salvage regimen. A total of 20 patients who fulfilled the inclusion criteria and who had RAL-based salvage therapy were assessed for clinical, immunological and virological response. The data were picked up from the electronic database of the center and analyzed.
RESULTS: Age, sex, date of initial diagnosis, date, and type of first line and second line regimens were documented, CD4 count, and plasma viral load at the time of initiation and after 3 and 6 months were recorded. Undetectable viral load was documented in all patients at 6 months. No noticeable adverse effects were noted.
CONCLUSION: This study clearly shows that RAL containing regimens have a high degree of effectiveness in treatment-experienced patients and show effective and durable suppression of viral load with low adverse effect rates and reliable long-term safety.

INTRODUCTION

Raltegravir (RAL), an HIV-1 integrase strand transfer inhibitor (InSTI) was the first drug in this class approved by the Food and Drug Administration for use as a part of combination antiretroviral therapy (ART), in October 2007.[1] The approval was based on results from two placebo-controlled randomized clinical trials, BENCHMRK-1 and BENCHMRK-2, which were conducted among HIV-infected ART-experienced patients with triple antiretroviral drug class resistance and limited treatment options. These studies found that RAL plus optimized background ART provided better HIV RNA suppression than optimized background therapy (OBT) alone.[23] The ANRS 139 Trio and the Merck EAP 0518 studies confirmed high rates of virologic suppression associated with the use of RAL-based antiretroviral regimens among ART-experienced patients with multidrug-resistant HIV infections.[45] Further studies among ART-naïve patients found that RAL-based combination treatment resulted in rapid and potent antiretroviral activity and was well tolerated,[6] leading to the recommendation for its use as a standard for initial treatment of HIV. RAL remains a recommended drug for ART-experienced patients who are InSTI-naïve and experience virologic nonsuppression or rebound or who desire regimen simplification.[7]

The use of InSTIs and drugs from other new classes, such as entry and fusion inhibitors, has increased steadily in the US in recent years.[8] However, studies on the use of RAL in immunological, virological, and clinical outcomes among ART-experienced patients are non-existent in the Indian context. RAL has been introduced by the National AIDS Control Programme as a salvage therapy rather recently; our center has been using this drug for the past 5 years. We sought to evaluate the clinical, immunological, virological outcomes in patients who failed second-line ART and were started on RAL as a part of salvage therapy.

METHODS

This was a retrospective, observational study of patients on ART who had suspected failure of second-line therapy using data collected at Apex Immunodeficiency Center, Base Hospital, New Delhi, India. Patients were considered for inclusion in this study if they were suspected of failing a second line ART regimen, which included 2–3 nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) and a protease inhibitor (PI) and were given RAL as a part of the salvage regimen. Second-line ART was defined as the regimen used for the treatment of patients living with HIV who failed a first-line regimen, and typically, it would consist of a PI (e.g., boosted Lopinavir or atazanavir) and two or three NRTIs (e.g., lamivudine and tenofovir/zidovudine/abacavir). Salvage regimen included the PI boosted with ritonavir (Lopinavir/r, Atazanavir/r) and the integrase inhibitor RAL, together with an NRTI backbone likely thought to be effective or on the basis of HIV genotyping results. Plasma viral load (PVL) and CD4 count testing were done at 3 months and 6 months from the date of starting salvage regimen. An undetectable PVL was defined as a result with fewer than 50 copies/ml. The treatment failure was defined as a PVL result of 1000 copies/ml in two consecutive results in a 3-month time frame. Adherence to therapy was strictly monitored by the team consisting of HIV physician, nurse, and the counseling team.

The data collected included the demographic, clinical information (treatment and laboratory data) of all patients on follow-up and stored into an electronic database in the center.

Prior permission of the Hospital Ethics Committee was obtained for the study. Informed consent from the patients was not obtained, as this was a study involving routinely collected data. The Hospital Ethics Committee was informed accordingly, and it waived the need for consent. CD4-positive T-cell counts were determined by flow cytometry using the FACSCalibur cytometer (Becton Dickinson, San Jose,

Calif, USA), and PVL was measured using the standard sensitive COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test, v2.0, which has a detection range of 50–10,000,000 copies/mL.

RESULTS

A total of 20 patients were put on RAL-based salvage regimen in our center. Three of them were female, and rest were male. Median age was 45.55 years (32–63). The maximum duration of therapy (ART) in these patients was 16 years. Minimum duration recorded was 6 months. Four patients were on Tenofovir-based therapy in the first line, while one was on stavudine base and rest of them on Zidovudine. One of the patients had HIV 2 and was accordingly on PIs, rest were on nevirapine[9] and efavirenz.[8] Tenofovir, lamivudine, and lopinavir/r were used in majority as second-line therapy except Abacavir in one, Emtricitabine in three and atazanavir/r in 04 of them depending on the patient profile, toxicity, and availability of drugs. Four patients were directly put on RAL-based salvage regimen as the condition of the patient was thought to be so poor as to be deemed beyond salvage, or the other drugs were found not suitable because of various contraindications. Clinical characteristics of patients before starting RAL-based salvage regimen, including the various opportunistic infections are depicted in Table 1.

Table 1

Clinical characteristics of patients started on raltegravir-based salvage regime

Age	Sex	Date of diagnosis	1st line ART	2nd line ART	Opportunistic infections/clinical profile
38	Male	January 2006	March 2006 (ZLN)	December 2012 (TLL/r)	Non-Hodgkin’s lymphoma, Stage IV
63	Female	January 2006	March 2007 (ZLN)	April 2012 (TLL/r)	PML, pancytopenia, disseminated TB
42	Male	June 2005	June 2008 (ZLN)	August 2013 (TLL/r)	Disseminated TB, HIV dementia, facial palsy (bilateral)
48	Male	October 2008	December 2008 (ZLN)	July 2012 (TLL/r)	Nil
42	Male	December 2009	January 2010 (ZLE)	September 2012 (TLA/r)	Chronic cryptosporidial diarrhea, fungal esophagitis
39	Male	October 2005	November 2005 (ZLN)	February 2012 (TEA/r)	Weight loss, recurrent oral ulcers
33	Male	June 2006	January 2008 (ZLE)	September 2012 (TLL/r)	Disseminated TB, bilateral cataract
33	Male	January 2011	January 2011 (ZLE)	March 2012 (TLL/r)	PML
49	Male	January 2006	April 2006 (ZLN)	May 2015 (ALL/r)	Chronic kidney disease, Stage V
57	Male	May 2010	June 2010 (ZLN)	October 2013 (TLL/r)	Disseminated TB
34	Male	February 2012	February 2012 (ZLN)	October 2012 (TEL/r)	Disseminated TB, tenofovir-induced RTA
42	Male	December 2004	January 2005 (ZLN)	October 2013 (TLL/r)	Pulmonary TB
55	Male	January 2015	January 2015 (TLE)		Carcinoma anal canal, tenofovir-induced RTA
56	Male	March 2015	March 2015 (TLE)		Tenofovir-induced RTA
53	Male	May 2005	March 2005 (SLN)	May 2011 (TEA/r)	PML
42	Female	April 2016	April 2016 (TLE)		Disseminated TB, PML
32	Male	December 2012	January 2013 (ZLE)	October 2014 (TLA/r)	Disseminated TB, severe anemia, CKD
40	Male	February 2014	February 2014 (TLL/r)		Chronic diarrhea, weight loss
62	Male	March 2008	March 2008 (ZLN)	November 2010 (TLL/r)	Cryptococcal meningitis, disseminated TB
51	Female	January 2010	January 2010 (ZLE)	April 2014 (TLL/r)	Disseminated TB, multidermatomal herpes zoster

ZLN=Zidovudine, lamivudine, nevirapine; ZLE=Zidovudine, lamivudine, efavirenz; TLE=Tenofovir, lamivudine, efavirenz; SLN=Stavudine, lamivudine, nevirapine; TLL/r=Tenofovir, lamivudine, lopinavir/ritonavir; TLA/r=Tenofovir, lamivudine, atazanavir/ritonavir; TEA/r=Tenofovir, emtricitabine, atazanavir/ritonavir; TEL/r=Tenofovir, emtricitabine, lopinavir/ritonavir; ALL/r=Abacavir, lamivudine, lopinavir/ritonavir; PML=Progressive multifocal leukoencephalopathy; TB=Tuberculosis; RTA=Renal tubular acidosis; CKD=Chronic kidney disease; ART=Antiretroviral therapy

The minimum CD4 count was documented to be 08 and maximum to be 323/μL and PVL to be ranging from 3 to 6 logs before starting the salvage regimen. The CD4 count and PVL measured after 3 and 6 months from the start of RAL-based regimen is as enumerated in Table 2. The rapid drop in viral load in majority at 3 months and reaching undetectable levels at 6 months was documented. CD4 count was not found to be rising in sync with dropping viral load was also noted. No noticeable side effects were noted directly attributable to RAL alone. All 20 patients are alive and healthy with undetectable viral loads and are on routine follow-up. Maximum follow-up of the patient on RAL based therapy is now 5 years.

Table 2

Immunological and virological parameters before and after raltegravir initiation

Before		After
CD4 count (mm3)	PVL (copies/ml)	CD4 count (3/6 months) (/mm3)	PVL (3/6 months) (copies/ml)
10	2.87×105	138/182	320/ND
118	8.79×104	193/NA	NA/ND
288	3.93×104	243/475	NA/ND
204	4.63×106	270/NA	1.5×10≥/ND
323	6.79×106	379/NA	50/ND
127	4.69×104	230/968	216/ND
122	5.62×106	431/504	197/ND
255	2.99×104	370/452	ND/ND
108	8.84×103	133/13	ND/ND
8	3.68×106	NA/91	65/ND
86	7.59×103	438/580	ND/ND
98	2.32×104	279/407	ND/ND
109	9.95×104	NA/17	NA/ND
73	2.79×105	NA/14	NA/ND
36	1.79×104	279/33	60/ND
74	1.77×104	NA/NA	NA/ND
95	7.44×105	108/29	2.07×10²/ND
100	8.73×104	NA/17	NA/ND
21	NA	NA/89	NA/ND
67	3.86×106	85/167	3.3×10²/ND

PVL=Plasma viral load; NA=Not available; ND=Not detected

DISCUSSION

The initial approval of RAL for use in HIV-infected, treatment-experienced patients was based on the BENCHMRK 1 and 2 trials; each was a large, multicenter, international trial with 699 patients combined. The BENCHMRK studies were Phase III, randomized, double-blind, placebo-controlled trials in HIV-infected patients with documented 3-class resistance (resistance to at least one NRTI, one non-NRTI, and one PI) and failing current ART. The primary endpoint was viral suppression at week 48, but the trial remained blinded to week 156. On completion of the double-blind portion, approximately 50% of patients in the original RAL treatment arms entered an open-label extension arm that reported outcomes at 240 weeks. These 240-week outcome data provide the most compelling evidence for the durability of RAL-containing regimens. Most patients who achieved suppression at week 48 continued to maintain suppression throughout the follow-up, supporting long-term efficacy of RAL-containing regimens.[23] Complete viral suppression was noted at 24 weeks in all patients in our series of patients. The only other placebo-controlled RAL trial that has published longer-term outcomes is Protocol 005, a Phase II, the dose-ranging study started before the BENCHMRK trials reporting 96-week data.[1011] This study consisted of four arms, three with differing RAL doses (200 mg, 400 mg, or 600 mg, administered twice daily) and one placebo comparator arm, each paired with OBT selected on the basis of resistance and antiretroviral treatment history. The patients in this study were also multidrug resistant with documented 3-class resistance. Neither tipranavir nor darunavir was allowed to be used as part of the OBT.

The study protocol specified a blinded design to week 24, at which time patients were allowed to continue or join in an open-label extension with RAL 400 mg twice daily for a total of 96 weeks. Ninety-four of the original 133 RAL patients continued into the open-label portion of the trial; 86 patients completed the 96 weeks of therapy. At the end of 24 weeks, approximately 60% of patients in the combined RAL arms achieved a viral load of less than 50 copies/mL. At week 48, this percentage fell to 55%, and at week 96, 48% remained suppressed. Nine patients who achieved less than 50 copies/mL at week 48 experienced viral rebound before week 96. Seven of the nine patients had a genotypic sensitivity score of 0, indicating extensive antiretroviral resistance. Surprisingly, the drop in viral load to undetectable levels noticed in our set of patients was much earlier as compared to this trial. A Korean study investigated HIV-1-infected adults, including 13 antiretroviral-naive patients and 15 antiretroviral-experienced patients, treated with RAL plus ABC/3TC or ZDV/3TC. Virological suppression was achieved in 12 of the 13 (92%) antiretroviral-naive patients within 24 weeks and all (100%) patients within 96 weeks.[9] This study has almost comparable results to the present set of patients. Khan et al. reported 47 patients with suspected second-line failure met the inclusion criteria. Twenty-nine of them (62%) responded to enhanced adherence support, had a subsequent undetectable PVL after a median duration of 3 months and remained on second-line ART. The other 18 patients had to be initiated on a third-line ART regimen, which consisted of darunavir-ritonavir, RAL, and one or more appropriate nucleoside or NRTIs, based on the results of HIV genotype testing. Of the 13 patients for whom follow-up PVL results were available, 11 achieved virological suppression after a median duration of 3 months on third-line ART (interquartile range: 2.5–3.0). No serious treatment-related adverse events were recorded.[12] The viral suppression rates observed at 12 weeks' period in this study are similar to our study as most of our patients too developed suppression by this time. Treatment-related side effects directly attributable to RAL were in line with our study.

CONCLUSION

This study clearly shows that RAL containing regimens have a high degree of effectiveness in treatment-experienced patients and show effective and durable suppression of viral load with low adverse effect rates and reliable long-term safety. RAL has demonstrated superior efficacy in clinical, immunological, and virological improvements as part of a salvage regimen.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.