No increase death rate in HIV positive people with renal dysfunction receiving tenofovir in Zambia

27 May 2014. Related: Side effects.

Polly Clayden, HIV i-Base

Tenofovir disoproxil fumarate (TDF) did not worsen renal function recovery nor increase death rate in HIV positive adults with renal dysfunction in a large Zambian cohort followed for 12 months.

Zambia introduced TDF as the preferred NRTI for first line therapy in the national programme in 2007 – one of the first countries in sub-Saharan Africa to do so.

An article in the 15 May edition of Clinical Infectious Diseases describes findings from an evaluation of changes in renal function and mortality in adults starting TDF or non-TDF-containing ART in Lusaka between 2007 and 2011. [1]

Lloyd Mulenga and colleagues, for IeDEA Southern Africa performed the analysis. Participants were included if they werer aged 16 years and above, started ART during this time period, and had documented baseline weight and serum creatinine results.

Using the chronic kidney disease-epidemiology (CKD-EPI) formula, the investigators catagorised renal function by estimated glomerular filtration rate (eGFR) as: normal, > 90; mild eGFR 60–89, moderate 30–59, or severe <29 mL/min/1.73m2.

They looked at the following outcomes: 1. renal function after 6 and 12 months of ART, 2. proportion of patients with moderate or severe eGFR decrease on ART and 3. death.

They used a multivariable mixed-effects model to compare the change in eGFR among participants receiving TDF and non-TDF regimens. Logistic and competing risk regression models were used to assess the odds of developing moderate or severe eGFR decrease and mortality, respectively. All analyses were adjusted for age, sex, calendar year, WHO stage, CD4 and haemaglobin.

The evaluation included 62,230 adults. Of these, 38,716 (62.2%) started a TDF-based regimen.

At baseline, participants receiving TDF started ART with more advanced HIV than those not receiving TDF, respectively 59.4% vs 47.7% were WHO stage 3 or 4. And they were more likely to receive efavirenz-based ART, respectively 60.4% vs16.6%.

Women were more likely to receive a non-TDF regimen than men, respectively 70.4% vs 56.5%, and to have started ART in earlier calendar years.

Overall, participants receiving TDF were more likely to have some renal dysfunction than those receiving non-TDF regimens at baseline, respectively 16.7% vs 12.4%. But double the proportion in the non-TDF than TDF group had moderate or severe renal dysfunction, respectively 4.0% vs 1.9%. All comparisons p<0.001.

After starting ART, 70.4% and 84.9% of participants receiving TDF and non-TDF regimens had at least one repeated creatinine measurement available after either 6 or 12 months on ART.

The investigators observed a slight decline in renal function in participants who started with no renal function at 6 and 12 months in both groups: -15 mL/min and -17 mL/min for those receiving TDF and non-TDF respectively. There was no change in those with mild eGFR decrease at baseline.

Adjusted analyses revealed slightly reduced renal function at 6 and 12 months in participants receiving TDF vs non-TDF based regimens.

There was a higher proportion of participants with no or mild renal dysfunction that had an incident episode of severe eGFR decrease at 6 to12 months in the TDF group but this was not statistically significant at either time point: respectively 0.28% vs 0.6%, p=0.26; and 0.24%vs 0.15%, p=0.2.

The difference was significant for moderate or severe eGFR: respectively 1.90% vs 1.27%, p<0.001; and 1.84% vs 1.37%, p=0.02. Although these comparisons reached statistical significance, the investigators noted that the numbers remained low.

Overall, participants with moderate (n=616) or severe (n=110) renal dysfunction at baseline experienced an improvement in renal function with ART. This included those who received TDF despite severe renal failure (+30mL/min after 12 months).

Adjusted analyses showed an association between marginally lower renal function at 12 months with baseline moderate renal dysfunction. But for participants with available data TDF use appeared to be associated with higher eGFR during follow up for those starting ART with severe renal dysfunction: adjusted difference 21.7 (95% CI 4.33 to 39.10) at 12 months.

Starting a TDF regimen did not increase the odds of progression from moderate to severe renal dysfunction: adjusted odds ratio 1.11 (95% CI 0.46 to 2.70).

Over 111,972 person-years of follow up there were 2,405 (6.2%) and 1,472 (6.3%) deaths documented in the TDF and non-TDF groups respectively. Loss to follow up was respectively 27.4% and 20.7% of participants.

Overall, severity of renal dysfunction starting ART predicted mortality risk: adjusted subhazard ratio (sHR) for severe vs no baseline eGFR decrease 2.00 (1.52 to 2.63), p<0.001.

There was no difference in mortality rates with moderate or severe eGFR decrease between participants receiving TDF vs non-TDF regimens: respectively adjusted sHR 0.79 (95% CI 0.58 to 1.07) and 0.89 (95% CI 0.52 to 1.52).

Other risk factors for mortality were: low CD4 count, anaemia, male sex and advanced clinical stage HIV, all <0.001.

Comment

This CID article is accompanied by a helpful and carefully considered commentary, which rightly states: “This is the largest study of its kind, and the authors should be commended for its successful completion in a region in which undertaking such studies is challenging”. [2]

Worth reading, the commentary emphasises the need for longer follow up and that careful monitoring of kidney function after starting TDF remains important to prevent development or progression of renal disease, particularly in the context of limited resources to provide ART for those who progress to end-stage renal disease.

The authors add, “The conundrum, however, lies in how patients should be monitored for kidney disease” and suggest future studies look at simple tools, such as the combination of serum creatinine-based GFR estimates and a urine dipstick to see if these could cost-effectively identify people at greatest risk of TDF-related toxicity.

They stress that, as with many ARVs, the benefit of TDF to the majority of patients must be weighed against the potential harm to a small minority.

References:

1. Mulenga L et al. Effect of baseline renal function on tenofovir-containing antiretroviral therapy outcomes in Zambia. Clinical Infectious Diseases, 58 (10), 15 May 2014.
   http://cid.oxfordjournals.org/content/58/10/1473.full.pdf+html
2. Estrella M M et al. Risks and benefits of tenofovir in the context of kidney dysfunction in sub-Saharan Africa. Clinical Infectious Diseases, 58 (10), 15 May 2014.
   http://cid.oxfordjournals.org/content/58/10/1481.full.pdf+html