Nucleoside-sparing regimens

Simon Collins, HIV i-Base

The increasing link between nucleoside analogues and lipoatrophy and increased potency of ritonavir-boosted protease inhibitors have led to a number of so-called nucleoside sparing strategies, both in treatment naïve and experienced patients.

Summary reports from the main studies are included below.

Many of the strategies below are not new in themselves and have usually resulted in poorer results than traditional two-nukes plus either an NNRTI or PI therapies. They are present only limited data, often from open label single arm studies.

Some of the most recently approved drugs (lopinavir/r and tenofovir) have brought expectations for antiviral efficacy to over 90% and provided durable responses and any new approaches have to at least meet this challenge – both in clinical practice and in clinical trials. The 96-week tenofovir study also presented at the meeting showed that this could be done with reduced lipoatrophy compared to d4T and both abacavir and 3TC are generally tolerable, involve a low pill count and are associated less with lipoatrophy than either of the thymidine analogues that were almost universally used and recommended previously.

In dropping both drug numbers and drug potency, certainly in treatment naïve patients, there has to be a very good advantage for why someone who can be adherent with generally more difficult to tolerate ritonavir-boosted BID regimens should be excluded from using generally more tolerable nucleosides – and so far these studies have not provided data to support this.

If you are relying on reduced numbers of drugs, it should be common sense that the drug levels achieved become that much more crucial, because you have additional antiviral activity to buffer and variability. The studies here also highlighted the importance of adequate PK – especially important given the drug-drug interactions between all PIs and NNRTIs.

It is difficult to know what to make of the boosted-indinavir monotherapy study. Patients were carefully monitored throughout and the study due to close if 2/12 patients had confirmed viral load rebound to >400 copies/ml. The results are remarkable, and compartmental penetration is considered within the study, but a patient advantage apart from reduced drug use is not clear, as tolerability of boosted PI regimens is largely related to the boosted-PI component of the therapy.

Lopinavir/r and efavirenz

Ferré presented preliminary 24-week results from the French BIKS single arm 48-week study of open-label lopinavir/r (LPV/r) and efavirenz (EFV) without nucleosides. Because of the interaction between these two drugs the lopinavir/r dose was increased to four capsules twice daily and efavirenz was given at the standard 600mg QD. [1]

Of the 86 patients enrolled, 65 were ARV-naïve and 21 ARV-experienced. Treatment-experienced patients had to be NNRTI-naïve and have fewer than five LPV/r-associated mutations. Mean baseline characteristics included CD4 cell count 307/mm3, mean viral load 4.84 log10 copies/ml and was >5 log in 42% of the pts.

Mean viral load reduction at week 24 was –3 logs with 87% of patients <400 cp/ml by ITT analysis and 76% reaching <50 copies/ml (Observed analysis – ITT not given). Mean CD4 increase was +162. Viral rebound occurred in four patients: two patients had blips (HIV RNA <400 cp/ml on subsequent control), one was not compliant and one had confirmed virologic failure.

After a median follow up of 36 weeks, premature discontinuation occurred in 14 pts: CNS side effects (n=3), cutaneous rash (n=3), non compliance or lost to follow up (n=3), others (n=5).

Grade 3/4 clinically relevant adverse events were seen in 34 patients (40%) including CNS symptoms (n=17), diarrhoea (n=11), cutaneous rash (n=4). Grade 3/4 hypercholesterolaemia, hypertriglyceridaemia and asymptomatic hepatic cytolysis have been observed in 29, 13 and three patients, respectively.

Median change in fasting triglycerides and total cholesterol at W24 was +0.88 and +0.62 g/l, respectively. Median increased in LDL/HDL ratio was +0.27 at W24.

Saquinavir/ritonavir plus lopinavir/r

Hellinger and colleagues reported 24 week virological and PK results from a Roche-sponsored pilot study using a dual-boosted PI combination of open label saquinavir/ritonavir 1,000mg/100mg BID together with lopinavir/r at regular dose BID in 20 PI-naïve patients. This study was again without background nucleosides, although two patients intensified treatment at week 12 by adding tenofovir dependent on protocol defined virological response. [2]

Mean baseline viral load and CD4 were 4.4 log and 274 cell/mm3 respectively. Only three women were enrolled, 40% of the patients were African-American and 85% were MSM.

Four patients discontinued (one due to hyperlipidaemia at week 36, on with GI distress at week 4. One case of none adherence and one person moved study centre). 14/16 people remaining on study medications at week 48 achieved viral suppression and two patients adding tenofovir also achieved <50 copies/ml. Plasma trough levels of lopinavir/r and all but one saquinavir level were above the IC50 for wild-type virus (70 ng/ml and 50 ng/ml respectively).

Mean weight gain was 3.9kg and occurrence of central fat accumulation was reported in 66% of the group (increased abdominal girth, and/or chest breast size) although DEXA scan was not included, with only one case of mild to moderate lipoatrophy.

Mean triglycerides increased from 231 mg/dl at baseline to 358 mg/dl, with most of the increase occurring in the first four weeks. Although the study did not report these as extreme, the majority of patients required monitoring and intervention according to NCEP guidelines.

Ritonavir-boosted indinavir plus efavirenz (with and without d4T)

Merck’s approach was to use indinavir/ritonavir (dosed at 800mg/100mg BID) together with efavirenz (at 600mg QD) with or without d4T in just under 100 PI- NNRTI- and d4T-naïve patients. Around 30% of the participants were women and 70% male. Mean baseline viral load was around 4.6 log and CD4 count was lower in the d4T-receiving arm 322 ±175 versus 407 ±234 respectively. [3]

At week 48, by ITT analysis (NC=F) viral load reductions to <400 and <50 were achieved in 34/47 (72%) and 25/47 (53%) for nucleoside-sparing compared to 33/46 (72%) and 28/46 (61%) with additional d4T.

Side-effects for the nuke-sparing and d4T arms respectively were: drug-related (66 and 54%), nervous system (23 and 33%), psychiatric, eg depression (9 and 11%), renal colic/urolithiasis (6 and 9%), and rash (13 and 11%). Discontinuations due to clinical and laboratory AEs were 15% and 2% for nuke-sparing and 11% and 2% for the d4T group.

Although the study concluded “at 48 weeks IDV/RTV+EFV yielded similar promising efficacy and safety data” p-values were not included in the abstract and, to this reviewer at least, including a nucleoside resulted in both increased viral suppression and fewer side effects. In a clinical setting most physicians would chose a nucleoside associated with fewer side effects.

Lopinavir/r plus saquinavir – PK and efficacy as salvage therapy

Data from using the dual boosted-PI regimen of lopinavir/r plus saquinavir (dosed at 1,000mg BID) without nucleosides (and without additional ritonavir boosting for saquinavir) was also presented from Schlomo Staszewski, this time in 63 heavily treatment experienced patients (13 women, 50 men) from the Frankfurt cohort, whose current regimen was virologically failing. A main focus of the study was intensive PK assessment, included to avoid exposure to suboptimal drug levels through drug-drug interactions. [4]

The rationale for this approach is necessarily very different because of the patient cohort, who had a median age of 42, 6.7 years antiretroviral experience and previous exposure to 10 drugs. Median baseline viral load and CD4 were 5.2 logs and 168 cells/mm3 respectively. Reductive therapy has been suggested to maintain patients with a regimen that has reduced pill burden and toxicity until newer agents become available, but also many if not all of these patients would be expected to have extensive nucleoside resistance.

At week 24, 52 (81%) patients were still on therapy. Median viral load was 2.1 log (range 1.0–6.0 log) and median CD4 count was 299 cells/mm3 (range 1–750). PK analysis showed that plasma concentration levels of LPV and SQV were lower in non-responders (AUCss –22%, Cmin –32%; AUCss –47%, Cmin –50%, respectively) compared to responders. Nonresponders also had lower pre-dose levels than responders: SQV 244 versus 903 ng/ml; LPV 3790 versus 4945 ng/ml.

Other factors associated with response were higher CD4 count at baseline (196 cells/mm3 versus 66 for non-responders), fewer PI mutations in the last failing regimen (two versus eight for non-responders) and less prior PI experience.

Boosted indinavir monotherapy maintains durable suppression

Finally, Humfer and colleagues reported remarkable 48-week results from stepping patients down to a single-boosted PI monotherapy by 12 patients with viral load <50 copies/ml. The rationale for the study was that boosted-PI regimens achieve drug levels that are considerable higher than the IC95 for wild-type virus. Indinavir is a drug that is known to penetrate CNS and genital compartments and plasma trough levels were optimised by TDM to 500-2,000 nM/l and adherence support confirmed with MEMS.

At baseline nucleosides were stopped and patients monitored at week two and then monthly for viral load (LQ=20 copies/ml), CD4, and activation markers (CD38 and HLA-DR), and at baseline and week 48 with DEXA. Viral load in semen was tested at baseline and weeks 24 and 48 and seminal mtDNA checked at the start and end of the study. Primary endpoint was either three consecutive viral load measurements >200 or two values >400 copies/ml within four weeks. Premature termination of the study was planned in case two patients would reach a primary endpoint.

Median pre-HAART CD4-count and viral load were 215 cells/mm3 5.0 log (3.6-6.6) respectively. At baseline, median CD4-count was 486/ml and patients had been using HAART for a mean 34 months.

None of the patients reached a primary endpoint. From a total of 138 viral load measurements, 5% were >50 copies (to between 50-100 in seven cases, to 100-200 in four cases (3/4 times was in one patient) and only once to >200 copies/ml). All increases were evenly spread throughout the 48-week study. Mean CD4 increase was 63 copies/mm3.

One patient developed T-cell lymphoma of the brain at week 24 and committed suicide at week 33. Four patients experienced nephrotoxicity despite TDM (three cases of urolithiasis and two increased creatinine).

No changes were detected from DEXA scans, and results from semen viral load and mtDNA that may offer clues for a caution or additional benefit were unfortunately not presented in the poster.


Unless stated otherwise, references are to the programme and abstracts of the 2nd IAS Conference on HIV Pathogenesis and Treatment, 13-16 July 2003, Paris.

  1. Ferré V, Allavena C, Poizot-Martin I et al – BIKS Study (lopinavir/ritonavir plus efavirenz combination): complete 24 week results. Abstract 36.
  2. Hellinger J, Cohen CJ, Morris AB et al – A pilot study of saquinavir-SGC (SQV) and lopinavir/ritonavir (LPV/r) twice daily in protease inhibitor (PI) naïve HIV-positive individuals: protease inhibitor concentrations and 24 week results. Abstract 571a.
  3. Stek Jr M, Hirschel B, Benetucci J et al – Comparison of boosted indinavir with efavirenz plus stavudine regimens in EASIER (European and South American Study of Indinavir, Efavirenz and Ritonavir). Abstract 39.
  4. Staszewski S, Dauer B, Von Hentig N et al – The LopSaq study: 24 week analysis of the double-PI salvage regimen containing lopinavir (LPV/r) plus saquinavir (SQV) without additional antiretroviral therapy. Abstract 583.
  5. Hupfer M, Wagels T, Kahlert C et al – Pilot study: ritonavir boosted indinavir treatment as a simplified maintenance ‘mono’-therapy for HIV infection. Abstract 589.

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